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1
Arty, Indyah Sulistyo. "SYNTHESIZE AND CITOTOXICITY TEST OF SEVERAL COMPOUNDS OF MONO PARA-HIDROXY CHALCON." Indonesian Journal of Chemistry 10, no. 1 (June 21, 2010): 110–15. http://dx.doi.org/10.22146/ijc.21489.
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Five compounds of mono para-hidroxy chalcon were synthesized (TC1, TC2, TC3, TC4, and TC5) and tested their cytotoxicity against HeLa cell and Raji cell. The difference in substituent of TC1 (R4 =H), TC2 (R4 = OCH3), and TC3 (R4 = F), showed the difference of their citotoxicity against HeLa cell. The citotoxicity of TC1 (LC50 = 16.08 µg/mL) ≈ TC3 (LC50 = 13.37 µg/mL), but the substituent difference of TC2 (LC50 = 147.43 µg/mL), decreasing it citotoxicity 10 times. Like wise their citotoxicity against Raji cell of TC1 (LC50 = 36.44 µg/mL) ≈ TC3 (LC50 = 30.46 µg/mL), but the substituent difference of TC2 (LC50 = 468.94 µg/mL), decreasing it citotoxicity activity 15 times. Nevertheless the strength of citotoxicity TC4 (LC50 = 98.74 µg/mL) and TC5 (LC50 = 110.97 µg/mL) against Raji cell are stronger than the citotoxicity of two of them against HeLa cell (LC50 of TC4 = none, LC50 of TC5 = 576.53 µg/mL). Keywords: mono para-hidroxy chalcon, HeLa cell, Raji cell, citotoxicity activity
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Uruilal, Costanza, Abraham Talahaturuson, Wihelmina Rumahlewang, and Jogeneis Patty. "ISOLASI Trichoderma spp. DAN DAYA ANTAGONISMENYA TERHADAP SCLEROTIUM ROLFSII SACC. PENYEBAB PENYAKIT LAYU PADA TANAMAN CABAI (Capsicum anuum) SECARA IN-VITRO." JURNAL BUDIDAYA PERTANIAN 13, no. 2 (December 1, 2017): 64–67. http://dx.doi.org/10.30598/jbdp.2017.13.2.64.
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The objective of this study is to isolation and agonistic test ability of Trichoderma spp. againts Sclerotium rolfsii Sacc. cause of wilting on pepper plants and has been conducted in Pathogenicity Laboratory Faculty of Agriculture Unpatti. The study use 5 treatment of isolate Trichoderma spp. (Tc3, Tc4, Tc5, Tc6 and Tc7) with 3 replications so that there are 15 experimental units. The results showed that the five isolates Trichoderma spp. has an antagonistic power to S. rolfsii with an average percentage of inhibition of S. rolfsii of 26,01%. Percentage of inhibition bolth of isolate ware not significantly different at 95% level test results between treatment. Average percentage inhibition of S. rolfsii by Trichoderma spp. each treatment was Tc6 = 27,31%, Tc3 = 26,63%, Tc5 = 26,05%, Tc7 = 25,69% and Tc4 = 24,37%.
 Keywords: antagonism, Trichoderma spp., Sclerotium rolfsii
 
 Abstrak
 Penelitian ini bertujuan mengisolasi dan menguji kemampuan antagonis Trichoderma spp. terhadap Sclerotium rolfsii Sacc. penyebab layu pada tanaman cabai dan telah dilaksanakan di Laboratorium Patogenisitas Fakultas Pertanian Unpatti, dengan menggunakan 5 perlakuan isolat Trichoderma spp. (Tc3, Tc4, Tc5, Tc6 dan Tc7) dengan 3 ulangan sehingga terdapat 15 satuan percobaan. Hasil penelitian menunjukkan bahwa kelima isolat Trichoderma sp. mempunyai daya antagonis terhadap S. rolfsii dengan rata-rata persentase penghambatan S. rolfsii sebesar 26%. Hasil analisis varians pada taraf 95% menunjukkan tidak ada perbedaan nyata antara perlakuan. Rata-rata persentase penghambatan S. rolfsii oleh Trichoderma spp. masing-masing perlakuan berturut-turut adalah Tc6 = 27,31%, Tc3 = 26,63%, Tc5 = 26,05%, Tc7 = 25,69% dan Tc4 = 24,37%, dengan rata-rata 26,01%.
 Kata kunci: antagonisme, Trichoderma spp., Sclerotium rolfsii
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Bagot, Martine, Hamid Echchakir, Fathia Mami-Chouaib, Marie-Hélène Delfau-Larue, Dominique Charue, Alain Bernheim, Salem Chouaib, Laurence Boumsell, and Armand Bensussan. "Isolation of Tumor-Specific Cytotoxic CD4+ and CD4+CD8dim+ T-Cell Clones Infiltrating a Cutaneous T-Cell Lymphoma." Blood 91, no. 11 (June 1, 1998): 4331–41. http://dx.doi.org/10.1182/blood.v91.11.4331.
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Abstract We have isolated several T-cell clones from lymphocytes infiltrating a human major histocompatibility class (MHC) II negative cutaneous T-cell lymphoma (CTCL). We describe here two of these clones, TC5 and TC7, with, respectively, a CD4+CD8dim+ and CD4+CD8− phenotype. Both clones mediated a specific MHC class I–restricted cytotoxic activity toward the fresh autologous tumor cells, and autologous tumor cell lines previously established with interleukin-2 (IL-2) and IL-7 from the skin and from the blood. Analysis of the T-cell receptor (TCR) Vβ gene expression showed that the tumor cells, which were shown to have a trisomy 7 by fluorescent in situ hybridization, expressed Vβ7/Jβ2.3, Vβ13/Jβ2.5, and Vβ22/Jβ2.5 rearrangements. Phenotypic analysis using specific anti-Vβ monoclonal antibodies indicated that only Vβ13 could be detected on the cell membrane of the tumor cells. Analysis of the TCR Vβ gene expression of the clones showed that TC5 and TC7 expressed a unique TCR-Vβ transcript, corresponding, respectively, to Vβ5/Jβ2.3 and Vβ17/Jβ2.7 gene segments. To determine whether these reactive T lymphocytes were present in vivo, we used specific primers corresponding to TC5- and TC7-Vβ TCR transcripts. The results showed that both cytotoxic T-cell clones were present at the lesional skin site and amplified in vitro. TC7 was found in the patient peripheral blood invaded by tumoral cells, whereas TC5 was not, indicating that the repertoire of the reactional lymphocytes differs in the blood and at the tumor site. These results show for the first time the presence of reactive T lymphocytes with CD4 or double-positive phenotype infiltrating a CTCL. These findings raise the question of the role of these antitumoral effector T cells in the tumor growth.
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Bagot, Martine, Hamid Echchakir, Fathia Mami-Chouaib, Marie-Hélène Delfau-Larue, Dominique Charue, Alain Bernheim, Salem Chouaib, Laurence Boumsell, and Armand Bensussan. "Isolation of Tumor-Specific Cytotoxic CD4+ and CD4+CD8dim+ T-Cell Clones Infiltrating a Cutaneous T-Cell Lymphoma." Blood 91, no. 11 (June 1, 1998): 4331–41. http://dx.doi.org/10.1182/blood.v91.11.4331.411k12_4331_4341.
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We have isolated several T-cell clones from lymphocytes infiltrating a human major histocompatibility class (MHC) II negative cutaneous T-cell lymphoma (CTCL). We describe here two of these clones, TC5 and TC7, with, respectively, a CD4+CD8dim+ and CD4+CD8− phenotype. Both clones mediated a specific MHC class I–restricted cytotoxic activity toward the fresh autologous tumor cells, and autologous tumor cell lines previously established with interleukin-2 (IL-2) and IL-7 from the skin and from the blood. Analysis of the T-cell receptor (TCR) Vβ gene expression showed that the tumor cells, which were shown to have a trisomy 7 by fluorescent in situ hybridization, expressed Vβ7/Jβ2.3, Vβ13/Jβ2.5, and Vβ22/Jβ2.5 rearrangements. Phenotypic analysis using specific anti-Vβ monoclonal antibodies indicated that only Vβ13 could be detected on the cell membrane of the tumor cells. Analysis of the TCR Vβ gene expression of the clones showed that TC5 and TC7 expressed a unique TCR-Vβ transcript, corresponding, respectively, to Vβ5/Jβ2.3 and Vβ17/Jβ2.7 gene segments. To determine whether these reactive T lymphocytes were present in vivo, we used specific primers corresponding to TC5- and TC7-Vβ TCR transcripts. The results showed that both cytotoxic T-cell clones were present at the lesional skin site and amplified in vitro. TC7 was found in the patient peripheral blood invaded by tumoral cells, whereas TC5 was not, indicating that the repertoire of the reactional lymphocytes differs in the blood and at the tumor site. These results show for the first time the presence of reactive T lymphocytes with CD4 or double-positive phenotype infiltrating a CTCL. These findings raise the question of the role of these antitumoral effector T cells in the tumor growth.
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Goux, Delphine, Jérôme D. Coudert, Diane Maurice, Leonardo Scarpellino, Grégoire Jeannet, Stefano Piccolo, Kathleen Weston, Joerg Huelsken, and Werner Held. "Cooperating pre–T-cell receptor and TCF-1–dependent signals ensure thymocyte survival." Blood 106, no. 5 (September 1, 2005): 1726–33. http://dx.doi.org/10.1182/blood-2005-01-0337.
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Abstract Intrathymic T-cell maturation critically depends on the selective expansion of thymocytes expressing a functionally rearranged T-cell receptor (TCR) β chain. In addition, TCR-independent signals also contribute to normal T-cell development. It is unclear whether and how signals from the 2 types of pathways are integrated. Here, we show that T-cell factor-1 (TCF-1), a nuclear effector of the canonical wingless/int (wnt)/catenin signaling pathway, ensures the survival of proliferating, pre-TCR+ thymocytes. The survival of pre-TCR+ thymocytes requires the presence of the N-terminal catenin-binding domain in TCF-1. This domain can bind the transcriptional coactivator β-catenin and may also bind γ-catenin (plakoglobin). However, in the absence of γ-catenin, T-cell development is normal, supporting a role for β-catenin. Signaling competent β-catenin is present prior to and thus arises independently from pre-TCR signaling and does not substantially increase on pre-TCR signaling. In contrast, pre-TCR signaling significantly induces TCF-1 expression. This coincides with the activation of a wnt/catenin/TCF reporter transgene in vivo. Collectively, these data suggest that efficient TCF-dependent transcription requires that pre-TCR signaling induces TCF-1 expression, whereas wnt signals may provide the coactivator such as β-catenin. The 2 pathways thus have to cooperate to ensure thymocyte survival at the pre-TCR stage. (Blood. 2005;106:1726-1733)
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Ciurea, Stefan O., Rima M. Saliba, Ulas D. Bayraktar, Susan Xie, Gabriela Rondon, Simrit Parmar, Partow Kebriaei, et al. "Improved Early Outcomes with T-Cell Replete (TCR) Compared with T-Cell Depleted (TCD) Haploidentical Stem Cell Transplantation (HaploSCT)." Blood 118, no. 21 (November 18, 2011): 320. http://dx.doi.org/10.1182/blood.v118.21.320.320.
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Abstract Abstract 320 Background: HaploSCT has been commonly performed with a TCD graft using CD34+ selection; however, this has been limited by a higher non-relapse mortality (NRM) primarily related to infectious complications. An alternative approach using a TCR bone marrow graft and high-dose post-transplant cyclophosphamide (HDPTCy) in the setting of non-myeloablative conditioning has been reported to have lower NRM and acceptable rates of GVHD. Methods: We hypothesized that TCR HaploSCT using HDPTCy is associated with improved immunologic reconstitution, less NRM and better early outcomes compared with TCD HaploSCT, and analyzed 65 consecutive patients (pts) treated at UTMDACC with the same conditioning regimen, fludarabine (40mg/m2/day × 4), melphalan (140mg/m2) and thiotepa (10mg/kg). TCD HaploSCT pts were treated between 2001 and 2009, while TCR patients after 2009. 6 pts in the TCR group >55 years/comorbidities received reduced doses of melphalan (100mg/m2) and thiotepa (5mg/kg). There was no GVHD prophylaxis in the TCD group, while TCR group received HDPTCy (50mg/kg/day × 2) followed by tacrolimus and mycophenolate. Results: The median follow-up was 10 months (range 3.5–25) for the TCR group and 44 (11–79) months for the TCD group. Median age was 45 years (range 20–63) in the TCR group and 36 years (range 18–56) in the TCD group (p=0.02). 28% were > 50 years in the TCR compared with 6% in the TCD group (p=0.02). Diagnoses were: AML/MDS 50% vs. 79%, ALL 13% vs. 12%, CML 16% vs. 6%, lymphoma/CLL 9% vs. 3% in the TCR vs. TCD groups, respectively. Only 13 (41%) and 12 (36%) of pts were in remission at transplant in both groups, respectively (p=0.7). 10/16 (62.5%) pts with AML/MDS in the TCR group had poor risk cytogenetics vs. 13/26 (50%) pts in the TCD group. The donors were 5/10 allele match in 20/32 (63%) and 16/31 (52%) in the two groups, respectively. Median numbers of CD34+ cells infused were 2.5×10e6/kg in the TCR group and 10.5×10e6/kg in the TCD group. All pts in the TCD group had peripheral blood selected CD34+ cells while all but one received bone marrow stem cells in the TCR group. One pt had early death in each group. Primary engraftment was achieved in 94% in the TCR group and 81% in the TCD group (p=0.1). Day-100 NRM for all pts was 9% in the TCR group vs. 21% for the TCD group, and for pts in remission at transplant 0% vs. 42%, respectively (p=0.01). NRM at 1 year for all pts was 16% for the TCR group vs. 42% for the TCD group (p=0.03) (Figure1), while for pts in remission was 0% vs. 67% (p=0.001). The cumulative incidences of grade II-IV aGVHD was 27% vs. 11% (p=0.5) and cGVHD was 8% vs. 18%, in the TCR and TCD group, respectively (p=0.03). OS and PFS at 1 year post-transplant were 66% vs. 30% (p=0.02) and 45% vs. 21% (p=0.03) for the whole group, and 92% vs. 33% (p=0.03) and 80% vs. 25% (p=0.02) for pts in remission at transplant, respectively (Figure1). Improved NRM in the TCR group was related to significantly better immunologic reconstitution of T-cell subsets. On day 30 post transplant there was a significantly better recovery of absolute CD4 cells in the TCR group (median 24 vs. 2, p=0.004) and CD8 cells (median 20.5 vs. 1.5, p=0.036). CD4 cells remained significantly lower in the TCD group until after day 180 when the median CD4 count was 200.5 vs. 64 in the TCR group (p=0.04) while the difference in CD8 counts became non-significantly higher in the TCR after day 90 (median 119 vs. 29, p=0.23). Conclusion: TCR HaploSCT is associated with better immunologic reconstitution and improved early outcomes compared with TCD HaploSCT. Disclosures: No relevant conflicts of interest to declare.
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Delea, Thomas, Aaron Moynahan, Wenzhen Ge, Xue Song, Glenn S. Kroog, Irene Noguera-Troise, Karen Rodriguez Lorenc, and Qiufei Ma. "Real-World Study of Patients with Triple-Class Exposed Relapsed/Refractory Multiple Myeloma: Analysis across a Spectrum of Advanced Disease Stage Medicare Patients in the United States." Blood 142, Supplement 1 (November 28, 2023): 3773. http://dx.doi.org/10.1182/blood-2023-188591.
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Background Treatment of relapsed/refractory (RR) multiple myeloma (MM) has been transformed by novel therapies including anti-CD38 monoclonal antibodies (mAb), 2 nd and 3 rd generation immunomodulatory drugs (IMiD), and proteasome inhibitors (PI). This has resulted in increasing numbers (no.) of triple-class exposed (TCE) patients (pts), defined as pts who have received an IMiD, ≥1 PI, and ≥1 anti-CD38 mAb. Many TCE pts are exposed to ≥5 drugs in these classes (i.e. penta-exposed [PE]: ≥2 IMID, ≥2 PI, and an anti-CD38 mAb). Some are refractory to ≥1 drug in each class (triple-class refractory [TCR]) and some are both PE and TCR (PE-TCR). Data on real-world outcomes for the spectrum of heavily pre-treated, advanced RRMM pts are limited. This study examined treatment patterns and healthcare resource utilization (HRU) and costs in Medicare-insured pts with TCE RRMM. Methods Adult pts with an incident diagnosis (Dx) of MM (≥2 outpatient claims 30-365 days apart OR ≥1 inpatient AND 6 months [mos.] of continuous eligibility prior to first Dx) during the study period (Nov 14, 2006-Dec 31, 2020) who were TCE were selected from the Center for Medicare and Medicaid Services Chronic Conditions Data Warehouse. TCE was defined as having ≥1 claim each for an IMiD, a PI, and an anti-CD38 mAb; PE was defined as having ≥2 claims each for an IMiD and a PI and ≥1 claim for an anti-CD38 mAb (TCE pts were assumed to have RRMM based on exposure). Pts were deemed TCR if refractory to ≥1 regimen each which included a PI, an IMiD, and an anti-CD38 mAb. Pts were considered refractory to a regimen if the period between the last claim or days supplied for any drug in the regimen and the start of the subsequent regimen was <60 days AND none of the drugs in the regimen were present in the next regimen. For each pt, the 1 st line of therapy (LOT) after becoming TCE was considered the index LOT and the date that this LOT initiated was defined as the index date. Pts were followed from the index date until the earliest of end of continuous enrollment or the end of study period. LOTs and treatment regimens were defined using an adaptation of published algorithm developed based on clinical expert opinion (Madduri et al. Future Oncol. 2021). Outcomes included anti-MM treatments received for index LOT, time to discontinuation (TTD), time to next treatment (TTNT), overall survival (OS), and post-index HRU and healthcare costs (adjusted to 2021 USD). Median TTD and OS were obtained by Kaplan-Meier (KM) methods. TTNT was analyzed by cumulative incidence methods with death as a competing risk. HRU and costs (in 2021 USD) were reported on a per patient per month (PPPM) basis. Results 137,707 pts with an MM Dx during the study period were identified. A total of 2,830 TCE, 1,371 TCR, 1,121 PE, and 774 PE-TCR pts met all other inclusion criteria. Mean age was 76 years in all 4 cohorts, 50-51% were female, 21% (TCR) to 29% (PE) had prior autologous stem cell transplant. The mean no. of prior LOTs ranged from 3.3 (TCE) to 4.5 (PE-TCR). The no. of new TCE pts increased almost 8-fold from 114 in 2016 to 890 in 2020; similar increases were observed for TCR, PE, and PE-TCR pts. Mean (SD) follow-up time (mos.) was 12.4 (10.6) for TCE, 11.9 (10.0) for TCR, 10.9 (10.3) for PE, and 10.1 (9.3) for PE-TCR. There was no apparent standard of care (SOC) treatment across the 4 cohorts; the most frequently used index LOT regimens were pomalidomide + daratumumab for TCE (17%) and PE (7%), pomalidomide + carfilzomib for TCR (10.3%), and pomalidomide + elotuzumab for PE-TCR (7.4%). In all 4 cohorts, pomalidomide was the most frequently received medication during the index LOT (32.6% [PE-TCR] to 43.3% [TCR]). Median TTD (mos.) ranged from 4.2 (PE-TCR) to 6.9 (TCE). Median TTNT (mos.) ranged from 8.1 (TCR) to 14.6 (TCE). Median OS (mos.) ranged from 13.0 (TCR) to 15.9 (PE). TCE pts had a mean PPPM 0.20 ED visits, 7.02 outpatient visits, 3.73 outpatient pharmacy claims, 0.14 hospitalizations, and 1.18 inpatient days. For TCE pts, mean PPPM total costs were $23,091, the largest share of which was for MM medications ($16,812), followed by other MM-related services ($4,824). Monthly HRU and costs for TCR, PE, and PE-TCR pts were similar to those for TCE. Conclusions Despite increasing no. of Medicare-insured TCE, TCR, PE, and PE-TCR MM pts, there is no apparent SOC treatment regimen. With current treatments, TTD, TTNT, and OS are short and HRU and costs are high. These data underscore the high unmet need for new therapies in this growing population.
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Sun, Hanli, Jiao Huang, Kai Zhan, Wanli Wu, Xianqing Tang, Min Liu, Shanshan Guo, Hongjun Zheng, Yingjie Huang, and Shi Zhong. "Abstract 3598: A new strategy for T cell therapy: T cells secreting TCR anti-CD3 bispecific T-cell engager." Cancer Research 84, no. 6_Supplement (March 22, 2024): 3598. http://dx.doi.org/10.1158/1538-7445.am2024-3598.
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Abstract TCR-engineered T (TCR-T) cells and TCR-anti-CD3 bispecific T-cell engagers (TCEs) are potent TCR-based therapeutic agents with distinct advantages and limitations in tumor treatment. TCR-T cells offer durable persistence within patients but necessitate personalized manufacturing and lack the capacity to harness bystander T cells. Conversely, TCEs are readily available as "off-the-shelf" products and can recruit bystander T cells, yet they exhibit a shorter lifespan. In our study, we sought to merge the merits of both approaches by engineering T cells to secrete a TCR-anti-CD3 TCE specific for alpha fetoprotein (AFP), a tumor-associated antigen abundantly expressed in hepatocellular carcinoma (HCC). We initially identified a TCR with specificity for the AFP158-166 peptide bound to HLA-A*02:01 and enhanced its affinity to picomolar via phage display. To facilitate efficient secretion by T cells, we adapted the high-affinity TCR to a single-chain format (scTCR) and fused it with a CD3-specific single-chain antibody fragment (scAFP-TCE). Our findings demonstrated that scAFP-TCE effectively redirected bystander T cells to engage in the lysis of HCC cells. Moreover, scAFP-TCE could be secreted by T cells transduced with lentiviral particles encoding the TCE gene. These transduced T cells exhibited potent antitumor activity both independently and by enlisting bystander T cells. This innovative T cell strategy, combining the bystander-recruiting ability of fusion proteins with the durable persistence seen in T cell therapy after a single infusion, presents a promising alternative to conventional TCR-based therapeutic agents. We anticipate that this novel approach may hold substantial potential for enhancing HCC treatment and expanding the scope of TCR-based immunotherapies. Citation Format: Hanli Sun, Jiao Huang, Kai Zhan, Wanli Wu, Xianqing Tang, Min Liu, Shanshan Guo, Hongjun Zheng, Yingjie Huang, Shi Zhong. A new strategy for T cell therapy: T cells secreting TCR anti-CD3 bispecific T-cell engager [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3598.
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Abdulazim, Amr, Nora Prochnow, and Tara Taeihagh. "TCR or Not TCR?" Journal of Oral and Maxillofacial Surgery 69, no. 10 (October 2011): 2483–84. http://dx.doi.org/10.1016/j.joms.2011.05.028.
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Oros-Ortega, Iván, Alejandro Alonso-López, Jesús Pérez-Moreno, Jorge C. López-Collado, Luis A. Lara-Pérez, Sandra E. Martínez-Garza, Laura Y. Solís-Ramos, and Antonio Andrade-Torres. "Respuesta de plántulas de Cedrela odorata a la inoculación con Rhizophagus intraradices y diferentes niveles de defoliación." Revista Mexicana de Ciencias Agrícolas 6, no. 3 (December 8, 2017): 627. http://dx.doi.org/10.29312/remexca.v6i3.645.
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 Respuesta de plántulas de Cedrela odorata a la inoculación con Rhizophagus intraradices y diferentes niveles de defoliación ; el efecto de seis tratamientos (T) sobre la tasa de crecimiento en altura (TCA) , diámetro ( TCD ) , tasa de crecimiento relativo (TCR ) y peso fresco y seco de plántulas de C. odorata se evaluaron en un vivero. Se utilizó un diseño completamente al azar con arreglo factorial (2 x 3); TS consistió en una combinación de los factores: porcentaje de defoliación (0, 50 y 90) y la inoculación de R. intraradices (con y sin inoculación). Después de seis meses, las plántulas de TS con la inoculación, independientemente del porcentaje de defoliación aplicada, mostraron más TCD (F= 100.45, p< 0,001) que TS sin inoculación. Las TS inoculadas, con diferentes niveles de defoliación, mostró el mayor TCA (F= 556.57 p< 0,001) después de tres meses. Sin embargo los últimos tres meses la interacción de la inoculación/ defoliación (50 y 90 %) indujo el mayor valor de TCA (F= 4.22 p< 0.01), y un crecimiento significativo en el peso fresco y seco de tallos, hojas y raíces. La inoculación produce altos niveles de micorrización en las raíces de C. odorata en el sexto mes. La defoliación al 90 % reduce significativamente la colonización de hifas y vesículas. Durante los tres primeros meses, las TS inoculadas mostraron el valor más alto de TCR, sin embargo, en los últimos tres meses los tratamientos sin inoculación y defoliación al 90% presentaron la mayor TCR. La interacción Inoculación / defoliación tiene efectos en el desarrollo de C. odorata, por lo que es conveniente considerar este tratamiento para la producción de plántulas en vivero.
 
 
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Blazar, BR, PA Taylor, JA Bluestone, and DA Vallera. "Murine gamma/delta-expressing T cells affect alloengraftment via the recognition of nonclassical major histocompatibility complex class Ib antigens." Blood 87, no. 10 (May 15, 1996): 4463–72. http://dx.doi.org/10.1182/blood.v87.10.4463.bloodjournal87104463.
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T cells with antidonor specificities have been isolated from human recipients experiencing graft rejection after allogeneic bone marrow transplantation (BMT). Partial T-cell depletion of unrelated BM grafts with an anti- T-cell receptor (TCR) monoclonal antibody (MoAb) directed against the TCR alpha/beta heterodimer have shown that the incidence of graft-versus-host disease is low and that the incidence of durable engraftment is high. These studies suggest either that the number of residual TCR alpha/beta+ cells was sufficient to permit alloengraftment or that the preservation of cells other than TCR alpha/beta+ cells was beneficial for engraftment. With respect to the latter, one such candidate cell is the TCR gamma/delta+ T cell. Because no studies have specifically examined whether TCR gamma/delta+ cells might be capable of eliminating BM-derived hematopoietic cells, we established a new graft rejection model system in which transgenic (Tg) H-2d mice (termed G8), known to express gamma/delta heterodimers on high proportion of peripheral T cells, were used as BMT recipients. These Tg TCR gamma/delta+ cells respond vigorously to target cells that express the nonclassical major histocompatibility complex (MHC) class lb region gene products encoded in H-2T region of H-2T(b)+ strains. G8 Tg mice were used as recipients for C57BL/6 (B6: H-2(b); H-2T(b)) T-cell- depleted (TCD) donor BM. We show that G8 Tg (H-2(d), H-2T(d)) mice are potent mediators of B6 BM graft rejection and that the rejection process was inhibited by anti-TCR gamma/delta MoAbs. In contrast, BM from a B6 congenic strain that expresses the H-2T(a) allele, B6.A- Tl(a)/BoyEg, was readily accepted, suggesting that H-2T antigens on repopulating donor BM cells are the targets of host graft rejecting T cells that express the TCR gamma/delta heterodimer. PB chimerism studies were performed at > or = 1.5 months post-BMT using TCD BM from severe combined immunodeficient allogeneic donors, which is highly susceptible to rejection by the host. The addition of donor G8 TCR gamma/delta+ cells to TCD donor BM was shown to significantly increase alloengraftment in B6 recipients. These results show that (1) host TCR gamma/delta+ cells can reject repopulating donor cells, presumably by responding to nonclassical MHC class lb gene products expressed on BM- derived hematopoietic progenitor cells; and (2) donor TCR gamma/delta+ cells can facilitate the alloengraftment of rigorously TCD donor BM.
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Kozovska, M. F., T. Yamamura, and T. Tabira. "T-T cellular interaction between CD4-CD8- regulatory T cells and T cell clones presenting TCR peptide. Its implication for TCR vaccination against experimental autoimmune encephalomyelitis." Journal of Immunology 157, no. 4 (August 15, 1996): 1781–90. http://dx.doi.org/10.4049/jimmunol.157.4.1781.
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Abstract Regulatory T cells recognizing TCR determinants presumably play a critical role in the control of experimental autoimmune encephalomyelitis, a prototype tissue-specific autoimmune disease. This study was initiated to determine whether regulatory T cells can be induced against a V beta 17a CDR2 peptide (residues 50-68) in SJL/J mice. Although the TCR peptide showed regulatory effects in vivo, the presence of T cells specific for the peptide could not be proven with conventional proliferation assays. Unexpectedly, in the presence of myelin basic protein-specific T clone cells (Tcc), the sensitized spleen cells vigorously proliferated in response to the TCR peptide. The subsequent experiment showed that this was due to the outstanding capability of the Tcc as APC for the exogenous TCR peptide. Using the Tcc as APC, we were able to establish V beta 17a50-68-specific T cell lines from in vivo primed spleen cells. The line cells were MHC class I restricted and dominated by T cells with a distinct surface phenotype (CD4-CD8-V beta 17a+). Presentation of the peptide by the Tcc was inhibited by treatment with gelonin that could block a MHC class I presentation pathway. The ability of T cells to present the TCR peptide was not related to their Ag specificity, but correlated with the expression levels of MHC class I molecules and adhesion molecules such as intercellular adhesion molecule-1 and B7-1 on their surface. The TCR peptide-specific T cells produced a soluble mediator(s) that is inhibitory for T cell activation and were protective against actively induced experimental autoimmune encephalomyelitis. These results show that V beta 17a50-68 vaccination induces regulatory CD4-CD8- T cells that could interact with T cells presenting relevant TCR fragments.
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Hohmann, Uwe, Winfried Busch, Katia Badaeva, Bernd Friebe, and Bikram S. Gill. "Molecular cytogenetic analysis of Agropyron chromatin specifying resistance to barley yellow dwarf virus in wheat." Genome 39, no. 2 (April 1, 1996): 336–47. http://dx.doi.org/10.1139/g96-044.
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Nine families of bread wheat (TC5, TC6, TC7, TC8, TC9, TC10, TC14, 5395-(243AA), and 5395) with resistance to barley yellow dwarf virus and containing putative translocations between wheat and a group 7 chromosome of Agropyron intermedium (L1 disomic addition line, 7Ai#1 chromosome) induced by homoeologous pairing or tissue culture were analyzed. C-banding, genomic in situ hybridization (GISH), and restriction fragment length polymorphism (RFLP) in combination with repetitive Agropyron-specific sequences and deletion mapping in wheat were used to determine the relative locations of the translocation breakpoints and the size of the transferred alien chromatin segments in hexaploid wheat–Agropyron translocation lines. All homoeologous compensating lines had complete 7Ai#1 or translocated 7Ai#1–7D chromosomes that substitute for chromosome 7D. Two complete 7Ai#1 (7D) substitution lines (5395-(243AA) and 5395), one T1BS–7Ai#1S∙7Ai#1L addition line (TC7), and two different translocation types, T7DS–7Ai#1S∙7Ai#1L (TC5, TC6, TC8, TC9, and TC10) and T7DS∙7DL–7Ai#1L (TC14), substituting for chromosome 7D were identified. The substitution line 5395-(243AA) had a reciprocal T1BS∙1BL–4BS/T1BL–4BS∙4BL translocation. TC14 has a 6G (6B) substitution. The RFLP data from deletion mapping studies in wheat using 37 group 7 clones provided 10 molecular tagged chromosome regions for homoeologous and syntenic group 7 wheat or Agropyron chromosomes. Together with GISH we identified three different sizes of the transferred Agropyron chromosome segments with approximate breakpoints at fraction length (FL) 0.33 in the short arm of chromosome T7DS–7Ai#1S∙7Ai#1L (TC5, TC6, TC8, TC9, and TC10) and another at FL 0.37 of the nonhomoeologous translocated chromosome T1BS–7Ai#1S∙7Ai#1L (TC7). One breakpoint was identified in the long arm of chromosome T7DS∙7DL–7Ai#1L (TC14) at FL 0.56. We detected some nonreciprocal translocations for the most proximal region of the chromosome arm of 7DL, which resulted in small duplications. Key words : C-banding, genomic in situ hybridization (GISH), physical mapping, translocation mapping, RFLP analysis.
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Dilchert, Janine, Martin Hofmann, Felix Unverdorben, Roland Kontermann, and Sebastian Bunk. "Mammalian Display Platform for the Maturation of Bispecific TCR-Based Molecules." Antibodies 11, no. 2 (May 10, 2022): 34. http://dx.doi.org/10.3390/antib11020034.
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Bispecific T cell receptor (TCR)-based molecules capable of redirecting and activating T cells towards tumor cells represent a novel and promising class of biotherapeutics for the treatment of cancer. Usage of TCRs allows for targeting of intracellularly expressed and highly selective cancer antigens, but also requires a complex maturation process to increase the naturally low affinity and stability of TCRs. Even though TCR domains can be matured via phage and yeast display, these techniques share the disadvantages of non-human glycosylation patterns and the need for a later reformatting into the final bispecific format. Here, we describe the development and application of a Chinese Hamster Ovary (CHO) display for affinity engineering of TCRs in the context of the final bispecific TCR format. The recombinase-mediated cassette exchange (RCME)-based system allows for stable, single-copy integration of bispecific TCR molecules with high efficiency into a defined genetic locus of CHO cells. We used the system to isolate affinity-increased variants of bispecific T cell engaging receptor (TCER) molecules from a library encoding different CDR variants of a model TCR targeting preferentially expressed antigen in melanoma (PRAME). When expressed as a soluble protein, the selected TCER molecules exhibited strong reactivity against PRAME-positive tumor cells associated with a pronounced cytokine release from activated T cells. The obtained data support the usage of the CHO display-based maturation system for TCR affinity maturation in the context of the final bispecific TCER format.
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Eyrich, Matthias, Tanja Croner, Christine Leiler, Peter Lang, Peter Bader, Thomas Klingebiel, Dietrich Niethammer, and Paul G. Schlegel. "Distinct contributions of CD4+ and CD8+naive and memory T-cell subsets to overall T-cell–receptor repertoire complexity following transplantation of T-cell–depleted CD34-selected hematopoietic progenitor cells from unrelated donors." Blood 100, no. 5 (September 1, 2002): 1915–18. http://dx.doi.org/10.1182/blood-2001-11-0005.
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Normalization of restricted T-cell–receptor (TCR) repertoire is critical following T-cell–depleted (TCD) stem cell transplantation. We present a prospective study analyzing respective contributions of naive and memory T-cell subsets within the CD4+ and CD8+ compartments to the evolution of overall TCR-repertoire complexity following transplantation of CD34-selected peripheral blood progenitor cells from unrelated donors. During the first year after transplantation, sorted CD4/45RA, CD4/45R0, CD8/45RA, and CD8/45R0 subsets were analyzed at 3-month intervals for TCR-repertoire complexity by CDR3 size spectratyping. Skew in TCR-repertoire was observed only in early memory-type T cells. CD4+ and CD8+ subsets differed in clonal distribution of CDR3 sizes, with rapid Gaussian normalization of bands in CD4/45R0+ T cells. Naive T cells displayed normal repertoire complexity and contributed significantly to skew correction. Our data provide direct evidence for an important role of de novo maturation of naive T cells in normalization of an initially restricted TCR-repertoire following transplantation of CD34-selected, TCD-depleted peripheral blood progenitors from unrelated donors.
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von Greyerz, Salome, Martin P. Zanni, Karin Frutig, Benno Schnyder, Christoph Burkhart та Werner J. Pichler. "Interaction of Sulfonamide Derivatives with the TCR of Sulfamethoxazole-Specific Human αβ+ T Cell Clones". Journal of Immunology 162, № 1 (1 січня 1999): 595–602. http://dx.doi.org/10.4049/jimmunol.162.1.595.
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Abstract Drugs like sulfamethoxazole (SMX) or lidocaine can be presented to specific human αβ+ T cell clones (TCC) by undergoing a noncovalent association with MHC-peptide complexes on HLA-matched APCs. For a better understanding of the molecular basis of the recognition of such drugs by specific TCC, we investigated 1) the fine specificity of the recognizing TCR, 2) the dose-response relationship for the induction of proliferation or cytokine production, and 3) the mechanism of TCR triggering. For that purpose, we tested the reactivity of 11 SMX-specific CD4+ TCC and 2 SMX-specific CD8+ TCC to a panel of 13 different sulfonamide derivatives bearing the same core structure. Five of 13 clones recognized only SMX, while all other clones were responding to as many as 6 different compounds. Some of the compounds needed up to two orders of magnitude higher concentrations than SMX to stimulate TCC, thereby displaying features of weak agonists. Different clones showed clear differences in the minimal drug concentration required for the induction of a proliferative response. Therefore, weaker or stronger agonistic properties were not a characteristic of a given sulfonamide derivative but rather an intrinsic property of the reacting TCR. Finally, the number of down-regulated TCRs was a logarithmic function of the ligand concentration, implicating that specific T cells were activated by serial TCR engagement. Our data demonstrate that, despite the special way of presentation, nonpeptide Ag like drugs appear to interact with the TCR of specific T cells in a similar way as peptide Ags.
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Cieslak, Cassandra, Carsten Hain, Christian Rückert-Reed, Tobias Busche, Levin Joe Klages, Katrin Schaper-Gerhardt, Ralf Gutzmer, Jörn Kalinowski, and Rudolf Stadler. "Nanopore Sequencing for T-Cell Receptor Rearrangement Analysis in Cutaneous T-Cell Lymphoma." Cancers 16, no. 21 (November 1, 2024): 3700. http://dx.doi.org/10.3390/cancers16213700.
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Background: Analysis of T-cell receptor (TCR) clonality is a major diagnostic tool for lymphomas, particularly for cutaneous T-cell lymphomas (CTCL) like Mycosis fungoides and Sézary syndrome. However, a fast and cost-effective workflow is needed to enable widespread use of this method. Methods: We established a procedure for TCR rearrangement analysis via Oxford Nanopore Technology (ONT) sequencing. TCR receptor rearrangements (TCR-gamma and TCR-beta chains) were analyzed in samples from 45 patients with various diagnoses: Mycosis fungoides (37/45), Sézary Syndrome (2/45), folliculotropic CTCL (1/45), and non-CTCL diagnoses as polyclonal controls (5/45). Sample types included formalin-fixed paraffin-embedded (FFPE) samples (27/45), fresh frozen samples (9/45), and CD3-isolated cells (9/45). In addition, DNA of a Jurkat cell line was used as a monoclonal control. TCR amplicons were generated employing an optimized version of the protocol from the Euro Clonality consortium. Sequencing was conducted on the ONT GridION and Illumina MiSeq platforms, followed by similar bioinformatic analysis protocols. The tumor clone frequency (TCF), a crucial prognostic factor for CTCL patients, was used for method comparison. Results: The use of an optimized amplicon protocol and adapted bioinformatic tools demonstrated a strong correlation in TCF values between both sequencing methods across all sample types (range R: 0.992–0.996; range r2: 0.984–0.991). Conclusions: In summary, ONT sequencing was able to detect TCR clonality comparable to NGS, indicating its potential as a faster and more cost-effective option for routine diagnostic use.
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Stasi, Antonio Di, LM Poon, Roberto Ferro, Denai Milton, Gabriela Rondon, Sa A. Wang, Amir Hamdi, et al. "Transplant Outcomes For Patients With AML/MDS Using Melphalan-Based Conditioning." Blood 122, no. 21 (November 15, 2013): 2167. http://dx.doi.org/10.1182/blood.v122.21.2167.2167.
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Abstract Introduction Haploidentical stem cell transplant (haplo-HCT) is a therapeutic option for patients without matched donors. We aimed to analyze outcomes of patients with AML/MDS treated with melphalan-based conditioning and different donors at our institution and determine the factors associated with survival. Methods All 246 patients receiving an allograft for AML/MDS between 01/2005 and 09/2012 were included in this retrospective analysis. Conditioning regimen consisted of melphalan 100 mg/m2 (Mel100) (N=37) or 140 mg/m2, (Mel140) (N=209) and fludarabine 120-240 mg/m2 +/- thiotepa (N=50). Graft versus host disease (GvHD) prophylaxis had consisted of tacrolimus and mini-methotrexate +/- ATG for matched transplants, and post-transplant cyclophosphamide (PTCy), tacrolimus and mycophenolate mofetil (MMF) for T-cell replete (TCR) haploidentical transplants. A small number of patients (N=19) received a T-cell depleted (TCD) haplo-HCT using CD34+ selected graft as previously described by us. We analyzed transplant outcomes and performed lymphocyte reconstitution on available samples from MRD, MUD and TCR-haplo recipients between day+30 and +365 post-transplant. Incidences in GvHD were assessed using Fisher's exact test. Differences in CD3+ T-cell counts were assessed using Kruskal-Wallis test. Kaplan-Meier survival curves were used to estimate OS, and PFS and the log-rank test was used to assess differences between groups; NRM was determined by the cumulative incidence (CI) function using the competing risks method. The competing risk included was relapse. Differences in cumulative incidence NRM between groups were assessed using Gray's test. Results Median follow-up for survivors was 31 months. PFS for the entire cohort at 1 year was 44% and OS was 53%. No differences in outcomes (NRM, relapse, PFS) were noted for patients treated with ablative (140 mg/m2) or reduced dose (100mg/m2) of melphalan, both overall and for patients in remission(Fig.1A). To appreciate the impact of different donor type of transplant outcomes we analyzed outcomes of patients treated in remission (CR1+CR2) (N=78). Pre-transplant characteristics were well balanced for patients who received a MSD, MUD or haplo donor except TCR haplo patients received almost exclusively a bone marrow graft (95%) and TCD-haplo patients had a younger median age at transplant (27.5 years; P=0.0004). For patients in remission at transplant, 1 year PFS was 67% (Mel100) vs. 69% (Mel140) (P=0.97). Based on donor type, the 1-year PFS were 80% for MRD (N=25) recipients, 76% for MUD (N=26) recipients, 64% for TCR haplo (N=19) and only 13% for TCD-haplo recipients (N=8) (P=0.003) (Fig.1B). In univariate and multivariable analyses for PFS, the only significant factors associated with worse survival were cytogenetic risk category and the use of a TCD haplo-HCT (Fig.1C). Using MUD donor as reference, no differences were detected in PFS when compared with recipients of MRD or TCR-haplodonors, while TCD-haplo group did significantly worse (multivariable analysis; P=0.006). The CI NRM rates for CR1+CR2 patients at 100 days were 0% (MRD), 5% (TCR-haplo), 4% (MUD), 38% (TCD-haplo), and at one year were 8% (MRD), 18% (TCR-haplo), 8% (MUD), and 75% (TCD-haplo) (P=0.0008). Incidence of severe aGvHD was 0% (TCR-haplo), 4% (MUD, MRD), and 50% (TCD-haplo) (P=0.0008). Overall chronic GvHD incidence was lowest in the TCR-haplo group (16%) and highest in the MRD group (48%). TCD-haplo and MUD had cGvHD rates of 25% and 34%, respectively (P=0.16). As shown in Fig.1D, TCR-haplo recipients reconstituted lymphocyte subsets with a kinetic trend similar to MUD and MRD recipients. All patients achieved normal CD3+ T-cell counts around day 180 post-transplant, with an early recovery of CD8+ T cells. TCR-haplo recipients did not have a significant inferior reconstitution for CD4+, CD8+, CD3-CD56+ and CD3-CD20+ cells at any time point between day 90 and day 365. Conclusions Outcomes of patients with AML/MDS treated with melphalan-based conditioning are negatively influenced by cytogenetic risk category and the use of a TCDhaplo donor, while melphalan dose and the use of a TCR haplo-HCT vs. matched donor did not negatively impact survival. Disclosures: No relevant conflicts of interest to declare.
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Halverson, David C., Gretchen N. Schwartz, Charles Carter, Ronald E. Gress, and Daniel H. Fowler. "In Vitro Generation of Allospecific Human CD8+ T Cells of Tc1 and Tc2 Phenotype." Blood 90, no. 5 (September 1, 1997): 2089–96. http://dx.doi.org/10.1182/blood.v90.5.2089.
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Abstract We have previously shown that allospecific murine CD8+ T cells of the Tc1 and Tc2 phenotype could be generated in vitro, and that such functionally defined T-cell subsets mediated a graft-versus-leukemia (GVL) effect with reduced graft-versus-host disease (GVHD). To evaluate whether analogous Tc1 and Tc2 subsets might be generated in humans, CD8+ T cells were allostimulated in the presence of either interleukin-12 (IL-12) and transforming growth factor-beta (TGF-β) (Tc1 culture) or IL-4 (Tc2 culture). Tc1-type CD8 cells secreted the type I cytokines IL-2 and interferon gamma (IFN-γ), whereas Tc2-type cells primarily secreted the type II cytokines IL-4, IL-5, and IL-10. Both cytokine-secreting populations effectively lysed tumor targets when stimulated with anti–T-cell receptor (TCR) antibody; allospecificity of Tc1- and Tc2-mediated cytolytic function was demonstrated using bone marrow–derived stimulator cells as targets. In addition, both Tc1 and Tc2 subsets were capable of mediating cytolysis through the fas pathway. We therefore conclude that allospecific human CD8+ T cells of Tc1 and Tc2 phenotype can be generated in vitro, and that these T-cell populations may be important for the mediation and regulation of allogeneic transplantation responses.
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Lan, Xin, Tian Mi, and Ben A. Youngblood. "Exhausted CD8 T cell progenitors are sustained with TCR engagement during anti-tumor responses." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 171.12. http://dx.doi.org/10.4049/jimmunol.210.supp.171.12.
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Abstract T cell exhaustion is a major contributor to tumor immune invasion. The durability of an anti-tumor response is in part determined by the persistence of exhausted CD8 T cell progenitors (Tpex) that reconstitute the effector T cell pool. While it has been reported that Tpex are able to survive without antigen, the role of TCR engagement in regulating Tpex self-renewal during tumor progression remains to be fully explored. Here, we used a Lewis lung carcinoma model where a robust or dampened TCR signal was elicited resulting in bona fide tumor-infiltrating Tpex. Longitudinal analysis of tumor-specific CD8 T cells revealed that robust TCR stimulation was required for the formation and maintenance of the Tpex reservoir in tumor-draining lymph nodes (tdLNs). Replenishment of tumor-infiltrating Tpex was abrogated by suboptimal priming despite a generation of central memory-like T cells in tdLNs. Moreover, attenuated TCR engagement substantially accelerated the terminal differentiation of optimally primed Tpex. Chromatin accessibility and whole genome DNA methylation profiling revealed that Tpex-associated epigenetic programs were significantly enriched in optimally engaged T cells in tdLNs. Additionally, tumor-infiltrating sub-primed Tpex gained more Ets1 motifs while Tpex established from robust TCR stimulation acquired greater chromatin accessibility at Tcf-1 targeting loci. These Tcf-1 targets were further validated to be Tpex-specific when compared to those in naive T cells. Collectively, our results highlight the importance of TCR engagement in sustaining Tpex during tumor progression.
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Werfel, T., M. Hentschel, A. Kapp, and H. Renz. "Dichotomy of blood- and skin-derived IL-4-producing allergen-specific T cells and restricted V beta repertoire in nickel-mediated contact dermatitis." Journal of Immunology 158, no. 5 (March 1, 1997): 2500–2505. http://dx.doi.org/10.4049/jimmunol.158.5.2500.
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Abstract In this study we compared the phenotype and cytokine patterns of nickel-specific T cell clones (TCC) derived from blood samples and positive patch test reactions. A total of 252 nickel-specific TCC were established from three nonatopic patients with allergic contact dermatitis caused by nickel. All TCC expressed the TCR-alpha beta, and 77% were CD4+ compared with 21% CD8+ TCC. In contrast to blood-derived TCC, the majority of skin-derived CD4+ or CD8+ T lymphocytes produced IL-4 either in combination with IFN-gamma (type 0 cytokine pattern) or IL-4 exclusively (type 2 pattern). Skin-derived nickel-specific TCC of each patient secreted significantly more IL-4 than blood-derived TCC of the same individual. Analysis of TCR-V beta repertoire from two patients indicated that &gt;40% of the tested TCC expressed one of the following V beta elements: V beta 13.1/13.2, V beta 20, V beta 2, V beta 6.7, or V beta 14. Only 20% of unstimulated T cells but &gt;40% of nickel-stimulated T cells derived from peripheral blood of the same individuals expressed these V beta elements, suggesting a selection of certain TCR-V beta elements by nickel sulfate in these patients. In contrast to the compartmentalization of IL-4 production, there were no major differences in the expression of TCR-V beta elements between blood- and skin-derived nickel-specific TCC. These results point to a modulation of the cytokine production pattern of T lymphocytes after their migration from peripheral blood into the skin and a production of the type 2 cytokine IL-4 in acute eczematous lesions in nonatopic individuals.
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Turtle, Cameron J., Jeff Delrow, Rochelle C. Joslyn, Hillary M. Swanson, Ryan Basom, Laura Tabellini, Colleen Delaney, Shelly Heimfeld, John A. Hansen та Stanley R. Riddell. "Innate signals overcome acquired TCR signaling pathway regulation and govern the fate of human CD161hi CD8α+ semi-invariant T cells". Blood 118, № 10 (8 вересня 2011): 2752–62. http://dx.doi.org/10.1182/blood-2011-02-334698.
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Abstract Type 17 programmed CD161hiCD8α+ T cells contribute to mucosal immunity to bacteria and yeast. In early life, microbial colonization induces proliferation of CD161hi cells that is dependent on their expression of a semi-invariant Vα7.2+ TCR. Although prevalent in adults, CD161hiCD8α+ cells exhibit weak proliferative and cytokine responses to TCR ligation. The mechanisms responsible for the dichotomous response of neonatal and adult CD161hi cells, and the signals that enable their effector function, have not been established. We describe acquired regulation of TCR signaling in adult memory CD161hiCD8α+ T cells that is absent in cord CD161hi cells and adult CD161lo cells. Regulated TCR signaling in CD161hi cells was due to profound alterations in TCR signaling pathway gene expression and could be overcome by costimulation through CD28 or innate cytokine receptors, which dictated the fate of their progeny. Costimulation with IL-1β during TCR ligation markedly increased proinflammatory IL-17 production, while IL-12–induced Tc1-like function and restored the response to TCR ligation without costimulation. CD161hi cells from umbilical cord blood and granulocyte colony stimulating factor-mobilized leukaphereses differed in frequency and function, suggesting future evaluation of the contribution of CD161hi cells in hematopoietic stem cell grafts to transplant outcomes is warranted.
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Migdał-Mikuli, Anna, and Elżbieta Szostak. "Phase Polymorphism of [Mn(DMSO)6](ClO4)2 Studied by Differential Scanning Calorimetry." Zeitschrift für Naturforschung A 60, no. 4 (April 1, 2005): 289–95. http://dx.doi.org/10.1515/zna-2005-0413.
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Abstract Six solid phases of [Mn(DMSO)6](ClO4)2 have been detected by differential scanning calorimetry. The phase transitions were found between the following solid phases: stable KIc ↔ stable KIb at TC5 = 225 K, metastable KIII ↔ metastable KII at TC4 = 322 K, stable KIb ↔ stable KIa at TC3 = 365 K, metastable KII↔overcooled K0 at TC2 = 376 K and stable KIa→stable K0 at TC1 = 379 K. The title compound melts at Tm = 488 K.
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Li, Kai, Yue Zhuo, Yue He, Fei Lei, Pengming He, Qin Lang, Dingxiu He, et al. "T cell receptor repertoire as a novel indicator for identification and immune surveillance of patients with severe obstructive sleep apnea." PeerJ 11 (April 7, 2023): e15009. http://dx.doi.org/10.7717/peerj.15009.
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Background Obstructive sleep apnea (OSA) is the most prevalent sleep disturbance that affects approximately 936 million people worldwide and leads to extensively increased incidence of cardiovascular disease, metabolic syndrome, neurological disorders, and traffic accidents. Severe OSA patients suffer a significantly higher risk of complications and worse comorbidity outcomes. Notwithstanding, with inadequate access to contact diagnosis based on polysomnography (PSG), numerous patients with severe sleep apnea have not been diagnosed, especially during the pandemic. Moreover, how the T cell immunity is impaired in OSA remains largely unknown. Methods We primarily investigated the T cell receptor (TCR) repertoires of 50 patients with severe OSA, 23 patients with mild-to-moderate OSA, 23 patients without OSA, and 157 healthy individuals, from their peripheral blood. Firstly, we compared the clinical characteristics, blood cell counts, the ratio of neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR), and CD4+/CD8+T cell count between groups. Then, we compared the diversity, clonotypes, unique VJ alleles in patients with different disease severity. Furthermore, by identifying a series of disease-associated amino acid sequences, we employed a repeated hold-out machine learning strategy to explore the optimal algorithm for calculating the TCR repertoire characteristic Index (OSA-TCI). We further confirmed its relation with clinical features by linear regression analysis. Moreover, in followup of severe OSA patients who accepted adherent non-invasive ventilation, we assessed the changes of TCR repertoires, OSA-TCI, ESS, NLR, PLR, and CD4+/CD8+T after therapy. Results We found an unexpected increase in diversity and clonotypes in the TCR repertoire of OSA patients. Furthermore, we successfully developed a novel indicator termed OSA-TCI to summarize the unique repertoire alteration, which provided 90% of sensitivity and 87% of specificity in distinguishing severe OSA. In rationalization, OSA-TCI was found correlated to AHI, BMI, hemoglobin, N1, N2 percentage of sleep, snoring, smoking and lowest oxygen saturation, but only independently related to AHI (R = 0.603) and smoking (R = 0.22). Finally, we observed OSA-TCI in the eight severe patients decreased significantly after home noninvasive ventilation for three months during follow-up, consistently in line with the TCR repertoire improvement. In contrast, NLR, PLR, and the ratio of CD4+/CD8+T cell count were found useless to diagnose and therapeutic surveillance of severe OSA. Conclusions Our study is the first to unveil the TCR repertoire alteration in OSA, indicates possible insidious autoimmune mechanisms underlying OSA, and suggests that TCR repertoires serve as a convenient peripheral blood biomarker for OSA assessment without long-time contact and facility/instrument occupation. It may shed light on future diagnostic, immunological, pathophysiological, and prognostic research on OSA.
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Li, Sheng-You, Ze-Kun Sun, Xue-Yi Zeng, Yue Zhang, Meng-Ling Wang, Sheng-Cao Hu, Jun-Rong Song, et al. "Potent Cytotoxicity of Novel L-Shaped Ortho-Quinone Analogs through Inducing Apoptosis." Molecules 24, no. 22 (November 15, 2019): 4138. http://dx.doi.org/10.3390/molecules24224138.
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Twenty-seven L-shaped ortho-quinone analogs were designed and synthesized using a one pot double-radical synthetic strategy followed by removing methyl at C-3 of the furan ring and introducing a diverse side chain at C-2 of the furan ring. The synthetic derivatives were investigated for their cytotoxicity activities against human leukemia cells K562, prostate cancer cells PC3, and melanoma cells WM9. Compounds TB1, TB3, TB4, TB6, TC1, TC3, TC5, TC9, TC11, TC12, TC14, TC15, TC16, and TC17 exhibited a better broad-spectrum cytotoxicity on three cancer cells. TB7 and TC7 selectively displayed potent inhibitory activities on leukemia cells K562 and prostate cancer cells PC3, respectively. Further studies indicated that TB3, TC1, TC3, TC7, and TC17 could significantly induce the apoptosis of PC3 cells. TC1 and TC17 significantly induced apoptosis of K562 cells. TC1, TC11, and TC14 induced significant apoptosis of WM9 cells. The structure-activity relationships evaluation showed that removing methyl at C-3 of the furan ring and introducing diverse side chains at C-2 of the furan ring is an effective strategy for improving the anticancer activity of L-shaped ortho-quinone analogs.
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Messier, H., H. Brickner, J. Gaikwad, and A. Fotedar. "A novel POU domain protein which binds to the T-cell receptor beta enhancer." Molecular and Cellular Biology 13, no. 9 (September 1993): 5450–60. http://dx.doi.org/10.1128/mcb.13.9.5450-5460.1993.
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POU domain proteins have been implicated in the regulation of a number of lineage-specific genes. Among the first POU domain proteins described were the immunoglobulin octamer-binding proteins Oct-1 and Oct-2. It was therefore of special interest when we identified a novel lymphoid POU domain protein in Southwestern (DNA-protein) screens of T-cell lambda gt11 libraries. This novel POU protein, TCF beta 1, binds in a sequence-specific manner to a critical motif in the T-cell receptor (TCR) beta enhancer. Sequence analysis revealed that TCF beta 1 represents a new class of POU domain proteins which are distantly related to other POU proteins. TCF beta 1 is encoded by multiple exons whose organization is distinct from that of other POU domain proteins. The expression of TCF beta 1 in a tissue-restricted manner and its ability to bind to multiple motifs in the TCR beta enhancer support a role in regulating TCR beta gene expression. The expression of TCF beta 1 in both B and T cells and the ability of recombinant TCF beta 1 to bind octamer and octamer-related motifs suggest that TCF beta 1 has additional roles in lymphoid cell function. The ability of TCF beta 1 to transactivate in a sequence-specific manner is consistent with a role for regulating lymphoid gene expression.
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Messier, H., H. Brickner, J. Gaikwad, and A. Fotedar. "A novel POU domain protein which binds to the T-cell receptor beta enhancer." Molecular and Cellular Biology 13, no. 9 (September 1993): 5450–60. http://dx.doi.org/10.1128/mcb.13.9.5450.
Full textAbstract:
POU domain proteins have been implicated in the regulation of a number of lineage-specific genes. Among the first POU domain proteins described were the immunoglobulin octamer-binding proteins Oct-1 and Oct-2. It was therefore of special interest when we identified a novel lymphoid POU domain protein in Southwestern (DNA-protein) screens of T-cell lambda gt11 libraries. This novel POU protein, TCF beta 1, binds in a sequence-specific manner to a critical motif in the T-cell receptor (TCR) beta enhancer. Sequence analysis revealed that TCF beta 1 represents a new class of POU domain proteins which are distantly related to other POU proteins. TCF beta 1 is encoded by multiple exons whose organization is distinct from that of other POU domain proteins. The expression of TCF beta 1 in a tissue-restricted manner and its ability to bind to multiple motifs in the TCR beta enhancer support a role in regulating TCR beta gene expression. The expression of TCF beta 1 in both B and T cells and the ability of recombinant TCF beta 1 to bind octamer and octamer-related motifs suggest that TCF beta 1 has additional roles in lymphoid cell function. The ability of TCF beta 1 to transactivate in a sequence-specific manner is consistent with a role for regulating lymphoid gene expression.
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Ajani, Emmanuel Kolawole, Olugbenga Orisasona, Oladeji Kazeem Kareem, Friday Elijah Osho, Aminat Omosalewa Adeyemo, Bamidele Oluwarotimi Omitoyin, and Abimbola Olumide Adekanmbi. "Growth Performance, Gut Ecology, Immunocompetence and Resistance of Oreochromis niloticus Juveniles Fed Dietary Curcumin longa." Croatian Journal of Fisheries 78, no. 3 (September 1, 2020): 145–56. http://dx.doi.org/10.2478/cjf-2020-0014.
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AbstractThe growth, gut ecology and immunocompetence of Oreochromis niloticus and the resistance to Aeromonas hydrophila were investigated after been fed with diets containing dietary Curcumin longa for 12 weeks. Diets were formulated to contain 30% crude protein with diet TC1, TC2, TC3, TC4 and TC5 having 0% (control), 0.25%, 0.5%, 0.75% and 1.0% turmeric powder, respectively. Diets were allotted to groups of O. niloticus (mean weight of 1.29± 0.15 g) and replicated thrice for 84 days. Results showed that the highest mean final weight (4.79±0.04 g) was obtained in TC3 and corresponded to the treatment with the highest feed intake. A significantly high (p<0.05) specific growth rate (SGR) was observed in TC3 (0.73±0.03 %day−1) while TC4 (0.57±0.02 %day−1) gave the lowest value. The highest microbial load in the gut was observed in TC1 groups and the least in TC4 groups. Red blood cell count, hemoglobin, packed cell volume did not show significant variation (p>0.05) across treatments. However, white blood cell (WBC) count was significantly higher in TC1 (control). There was an improved immunocompetence, as aspartate aminotransferase (AST) progressively reduces in fish fed supplements. Similarly, there was a better oxidative response in the treated groups with reduced hydrogen peroxidase, increased total protein and glutathione peroxidase. Mortality ranged from 25% in TC4 to 95% in TC1 after the challenge test with A. hydrophila. This study showed that C. longa inclusion at 0.5% is more beneficial when growth and health status of O. niloticus juveniles are considered.
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Trop, Sébastien, Michele Rhodes, David L. Wiest, Patrice Hugo та Juan Carlos Zúñiga-Pflücker. "Competitive Displacement of pTα by TCR-α During TCR Assembly Prevents Surface Coexpression of Pre-TCR and αβ TCR". Journal of Immunology 165, № 10 (15 листопада 2000): 5566–72. http://dx.doi.org/10.4049/jimmunol.165.10.5566.
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Van de Wetering, M., J. Castrop, V. Korinek, and H. Clevers. "Extensive alternative splicing and dual promoter usage generate Tcf-1 protein isoforms with differential transcription control properties." Molecular and Cellular Biology 16, no. 3 (March 1996): 745–52. http://dx.doi.org/10.1128/mcb.16.3.745.
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Previously, we reported the isolation of cDNA clones representing four alternative splice forms of TCF-1, a T-cell-specific transcription factor. In the present study, Western blotting (immunoblotting) yielded a multitude of TCF-1 proteins ranging from 25-55 kDa, a pattern not simply explained from the known splice alternatives. Subsequent cDNA cloning, PCR amplification, and analysis by rapid amplification of 5' cDNA ends revealed (i) the presence of an alternative upstream promoter, which extended the known N terminus by 116 amino acids, (ii) the presence of four alternative exons, and (iii) the existence of a second reading frame in the last exon encoding an extended C terminus. Inclusion of the extended N terminus into the originally reported protein resulted in a striking similarity to the lymphoid factor Lef-1. Several of the TCF-1 isoforms, although less potent, mimicked Lef-1 in transactivating transcription through the T-cell receptor alpha-chain (TCR-alpha) enhancer. These data provide a molecular basis for the complexity of the expressed TCF-1 proteins and establish the existence of functional differences between these isoforms. Furthermore, the functional redundancy between Tcf-1 and Lef-1 explains the apparently normal TCR-alpha expression in single Tcf-1 or Lef-1 knockout mice despite the firm in vitro evidence for the importance of the Tcf/Lef site in the TCR-alpha enhancer.
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Li, Yiming, Wenbin Zhao, Ying Shen, Yingchun Xu, Shuqing Chen, and Liqiang Pan. "T Cell Receptor-Directed Bispecific T Cell Engager Targeting MHC-Linked NY-ESO-1 for Tumor Immunotherapy." Biomedicines 12, no. 4 (April 1, 2024): 776. http://dx.doi.org/10.3390/biomedicines12040776.
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Antibody-based bispecific T cell engagers (TCEs) that redirect T cells to kill tumor cells have shown a promising therapeutic effect on hematologic malignancies. However, tumor-specific targeting is still a challenge for TCEs, impeding the development of TCEs for solid tumor therapy. The major histocompatibility complex (MHC) presents almost all intracellular peptides (including tumor-specific peptides) on the cell surface to be scanned by the TCR on T cells. With the premise of choosing optimal peptides, the final complex peptide–MHC could be the tumor-specific target for TCEs. Here, a novel TCR-directed format of a TCE targeting peptide–MHC was designed named IgG-T-TCE, which was modified from the IgG backbone and prepared in a mammalian cell expression system. The recombinant IgG-T-TCE-NY targeting NY-ESO-1157–165/HLA-A*02:01 could be generated in HEK293 cells with a glycosylated TCR and showed potency in T cell activation and redirecting T cells to specifically kill target tumor cells. We also found that the in vitro activity of IgG-T-TCE-NY could be leveraged by various anti-CD3 antibodies and Fc silencing. The IgG-T-TCE-NY efficiently inhibited tumor growth in a tumor–PBMC co-engrafted mouse model without any obvious toxicities.
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Vantellini, Alessio, Nora Wettstein, Melissa Vrohlings, Stephanie Jungmichel, André Luis Fonseca da Silva, Alice Langer, Anna Howald, et al. "Abstract 3494: Durable and potent in vitro T cell activity with repeated exposure to CDR404, a potential best-in-class T cell engager targeting MAGE-A4." Cancer Research 85, no. 8_Supplement_1 (April 21, 2025): 3494. https://doi.org/10.1158/1538-7445.am2025-3494.
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Abstract T cell engagers (TCEs) targeting the melanoma antigen gene A4 (MAGE-A4) have entered first-in-human trials for HLA-A*02:01+ patients with MAGE-A4 expressing solid tumors. CDR404 is a bispecific antibody-based TCE that binds bivalently to the MAGE-A4230-239 peptide on HLA-A*02:01 and monovalently to CD3. The safety, tolerability and preliminary therapeutic efficacy of CDR404 are currently being evaluated in a dose-finding Phase 1 trial in multiple solid cancers including NSCLC (NCT06402201). The only other MAGE-A4 targeting TCE currently in clinical trial is a TCR-based TCE with a low affinity T cell recruiter, bearing an Fc region (TCR-TCE-Fc). Therefore, there are fundamental differences in format, functionality and pharmacology between these two TCE molecules. This preclinical study provides novel mechanistic insights into the persistence of cancer cell killing with repeated dosing of CDR404, comparing it to the TCR-TCE-Fc molecule. Since upregulation of PD-1 is an obligate immunosuppressive brake to T cell activation, we additionally investigated the in vitro killing activity of a CDR404 and Pembrolizumab combination compared to CDR404 alone. In co-culture assays of MAGE-A4+/HLA-A*02:01+ NSCLC cells (NCI-H1755) and human PBMCs, CDR404 induced higher levels of T cell activation, reflected by activation (CD69, CD25) and proliferation (Ki67) markers, and more potent tumor cell killing compared to the TCR-TCE-Fc. Higher potency of CDR404 was confirmed on different MAGE-A4+ cell lines from various cancer types. CDR404 also showed more efficient cancer cell killing than the TCR-TCE-Fc at low E:T ratios (down to 1:1), indicating that it has the potential to achieve higher efficacy in tumors with low T cell infiltration (“cold tumors”). Strikingly, potency of CDR404 was efficiently maintained over multiple rounds of serial killing of NSCLC cells (NCI-H1755), in contrast to the TCR-TCE-Fc molecule. In this experiment, CDR404 induced significantly less upregulation of T cell exhaustion markers than the TCR-TCE-Fc. These results highlight the potential of CDR404 to achieve more durable responses in solid tumors. Since T cell engagers treatment is accompanied by upregulation of PD-1/PD-L1 axis, we evaluated CDR404 in combination with the anti-PD-1 therapy pembrolizumab, showing enhanced potency of in vitro exhausted T cells on a PD-L1 overexpressing NSCLC cell line compared to CDR404 alone. In conclusion, these results demonstrate the potential of CDR404 to achieve improved efficacy and more durable responses for HLA-A*02:01+ patients with MAGE-A4+ tumors. The combination with an anti-PD-1 therapy may have additive anti-tumor activity in patients, and could potentially allow a transition into earlier, anti-PD-1/PD-L1 containing lines of treatment for multiple solid cancers including NSCLC, thus benefiting a larger patient population. Citation Format: Alessio Vantellini, Nora Wettstein, Melissa Vrohlings, Stephanie Jungmichel, André Luis Fonseca da Silva, Alice Langer, Anna Howald, Zoi Barou, Daniel Lenherr-Frey, Matteo Morotti, Christian Leisner, Swethajit Biswas, Leonardo Borras. Durable and potent in vitro T cell activity with repeated exposure to CDR404, a potential best-in-class T cell engager targeting MAGE-A4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3494.
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Dempsey, Laurie A. "TCR tuning." Nature Immunology 13, no. 6 (May 18, 2012): 533. http://dx.doi.org/10.1038/ni.2335.
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Bell, Elaine. "TCR docking." Nature Reviews Immunology 2, no. 9 (September 2002): 626. http://dx.doi.org/10.1038/nri898.
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Jones, Daniel S., Peter Reichardt, Mandy L. Ford, Lindsay J. Edwards, and Brian D. Evavold. "TCR Antagonism by Peptide Requires High TCR Expression." Journal of Immunology 181, no. 3 (July 18, 2008): 1760–66. http://dx.doi.org/10.4049/jimmunol.181.3.1760.
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Sasmal, Dibyendu K., Wei Feng, Sobhan Roy, Peter Leung, Yanran He, Chufan Cai, Guoshuai Cao, et al. "TCR–pMHC bond conformation controls TCR ligand discrimination." Cellular & Molecular Immunology 17, no. 3 (September 17, 2019): 203–17. http://dx.doi.org/10.1038/s41423-019-0273-6.
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Abstract A major unanswered question is how a TCR discriminates between foreign and self-peptides presented on the APC surface. Here, we used in situ fluorescence resonance energy transfer (FRET) to measure the distances of single TCR–pMHC bonds and the conformations of individual TCR–CD3ζ receptors at the membranes of live primary T cells. We found that a TCR discriminates between closely related peptides by forming single TCR–pMHC bonds with different conformations, and the most potent pMHC forms the shortest bond. The bond conformation is an intrinsic property that is independent of the binding affinity and kinetics, TCR microcluster formation, and CD4 binding. The bond conformation dictates the degree of CD3ζ dissociation from the inner leaflet of the plasma membrane via a positive calcium signaling feedback loop to precisely control the accessibility of CD3ζ ITAMs for phosphorylation. Our data revealed the mechanism by which a TCR deciphers the structural differences among peptides via the TCR–pMHC bond conformation.
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Huang, Jun, and Dibyendu K. Sasmal. "TCR-pMHC bond length controls TCR ligand discrimination." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 184.10. http://dx.doi.org/10.4049/jimmunol.202.supp.184.10.
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Abstract T-cell receptors (TCRs) detect specifically and sensitively a small number of agonist peptide-major histocompatibility complexes (pMHCs) from an ocean of structurally similar self-pMHCs to trigger antigen-specific adaptive immune responses. Despite intense efforts, the mechanism underlying TCR ligand discrimination remains a major unanswered question in immunology. Here we show that a TCR discriminates between closely related peptides by forming TCR-pMHC bonds with different lengths, which precisely control the accessibility of CD3ζ immunoreceptor tyrosine-based activation motifs (ITAMs) for phosphorylation. Using in situ fluorescence resonance energy transfer (FRET), we measured the intermolecular length of single TCR-pMHC bonds and the intramolecular distance of individual TCR-CD3ζ complexes at the membrane of live primary T cells. We found that an agonist forms a short TCR-pMHC bond to pull the otherwise sequestered CD3ζ off the inner leaflet of the plasma membrane, leading to full exposure of its ITAMs for strong phosphorylation. By contrast, a structurally similar weaker peptide forms a longer bond with the TCR, resulting in partial dissociation of CD3ζ from the membrane and weak phosphorylation. Furthermore, we found that TCR-pMHC bond length determines 2D TCR binding kinetics and affinity, T-cell calcium signaling and T-cell proliferation, governing the entire process of signal reception, transduction and regulation. Thus, our data reveal the fundamental mechanism by which a TCR deciphers the structural differences between foreign antigens and self-peptides via TCR-pMHC bond length to initiate different TCR signaling for ligand discrimination.
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Bariana, Manpreet, Mark Batistick, Mathias Oelke, Sojung Kim, Elena Cassella, Sidharth Anand, Shaina Anuncio, et al. "Ex Vivo Enriched Tumor Antigen-Specific T Cells Are Optimal Effectors of T Cell Engagers and Tumor-Specific T Cell Receptor/T Cell Engager Combination Provides Synergistic Efficacy Against Hematologic Malignancies." Blood 142, Supplement 1 (November 28, 2023): 2056. http://dx.doi.org/10.1182/blood-2023-179342.
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Multiple myeloma (MM) and acute myeloid leukemia (AML) are blood cancers that remain difficult to treat because a large proportion of patients have disease that does not respond to currently available therapies. NexImmune's Artificial Immune Modulation (AIM) platform mimics natural dendritic cell function by using nanoparticles engineered with MHC molecules loaded with tumor specific peptides (signal 1) and anti-CD28 (signal 2) for activation and expansion of HLA A*02:01 restricted tumor associated antigen (TAA)-specific cytotoxic CD8 T lymphocytes (CTL). Additionally, T cell engager (TCE) therapy allows for TAA-specific, but T cell receptor (TCR) independent T cell cytotoxicity mediated by immunological synapse formation between targeted cancer cells and T cells. Given that T cell function in MM and AML patients is often perturbed and the response to TCE therapy is determined by pre-existing endogenous T cells of the patient, we hypothesized adoptively transferred multi-antigen specific T cells with a rejuvenated phenotype in combination with TCE therapy might produce optimal efficacy. We compared polyclonal CTL with AIM CTL (CTL that were AIM primed and expanded for optimal antigen experience and specificity). We evaluated the preclinical efficacy of B cell maturation antigen (BCMA)xCD3 TCE+MM-specific AIM CTL combination therapy and CD123xCD3 TCE+AML-specific AIM CTL combination therapy both in vitro and in vivo. In co-culture assays with polyclonal CTL and AIM CTL, we investigated the effect of prior antigen exposure on the efficacy of the TCE against tumor cell lines by measuring the responses to T cells alone and in the presence of TCE treatment. We quantified tumor cell survival and thus determined cytotoxicity of the various culture conditions by luciferase assay. Our analysis showed that, as expected, CD4 T cells had little potency. Non-HLA matched control CTL (bulk or enriched for naïve cells) without TCE showed higher cytotoxicity (data not shown), but these cells were much less potent than AIM CTL (data not shown and Fig. 1A). Combined TCR and TCE-mediated target cell killing was most efficient when using AIM CTL as effector cells (Fig. 1B). Correcting the data for TCR mediated killing revealed that antigen-experienced AIM CTL were indeed superior effectors of TCE potency than antigen inexperienced control CTL. This finding was reproducible regardless of the HLA type of the target cells, consistent with the TCR independent mechanism of action of TCE-mediated killing. Nuclear factor of activated T cells (NFAT) transcriptional reporter assays with Jurkat effector cells and AML target cells revealed that TCE treatment decreased NFAT transcriptional activity in TCE effector cells; moreover, TCE treatment in vivo (treating mice with AIM CTL +/- TCE) increased CD3 levels on AIM CTL. Both observations are consistent with reduced TCR mediated T cell activation in the context of TCE therapy. Furthermore, BCMAxCD3 TCE treatment of mice in a MM xenograft model resulted in decreased PD-1 expression on AIM CTL and enhanced the in vivo efficacy of AIM CTL. Our studies show that AIM CTL display strong anti-tumor activity, and even subtherapeutic AIM CTL cell doses can be highly efficacious when armed with a TCE. Importantly, our data indicate that AIM CTL cells are optimal TCE effectors, superior to less experienced, polyclonal CTL (such as the patient's endogenous T cells). Combining AIM CTL with TCE therapy has the additional benefits of complementary targets and mechanisms of action, reducing the risk of immune escape. Moreover, our preclinical studies suggest that TCE treatment reduces NFAT transcriptional activity and PD-1 induction associated with physiological TCR mediated T cell activation. This suggests that TCE mediated T cell activation can partially suppress TCR mediated T cell activation in AIM CTL, resulting in excellent tumor-specific cytolytic activity while inducing a transcriptional signature that preserves T cell fitness. Following withdrawal of TCE therapy, less exhausted AIM CTL will be present, facilitating the persistence of long-lasting anti-tumor activity and immunosurveillance. Combination of AIM CTL (autologous or HLA matched allogeneic) with TCE therapy is therefore a highly promising and innovative strategy for the induction of durable antitumor activity, and this approach has potential for clinical translation as a novel combinatorial immunotherapy.
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Wu, Ying, Maxwell Spurrell, Songyan Deng, and Kevan Herold. "Single-cell transcriptomics of CD8 T cells in autoimmune diabetes after anti-CD3 monoclonal antibody treatment." Journal of Immunology 212, no. 1_Supplement (May 1, 2024): 0998_4625. http://dx.doi.org/10.4049/jimmunol.212.supp.0998.4625.
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Abstract The FcR non-binding anti-CD3 mAb, teplizumab is the first drug approved by FDA to delay Type 1 diabetes (T1D) by modulating the immune mediated destruction of insulin-producing β cells. However, we and others have observed that after remission is induced in diabetic NOD mice that are treated with F(ab’)2 fragments of mAb 145-2C11, insulitis remains. To understand how the antibody induces long-term tolerance, we performed single-cell RNA-seq and TCR-seq on T cells from the islets and pancreas-draining lymph nodes (pLN) of long-term remitted NOD mice treated by anti-CD3 mAb or pre-diabetic NOD mice with insulitis. In the islets, CD8 T cells of remitted NOD had higher expressions of TCF-1 and EOMES, than their counterparts from pre-diabetic control. Notably, CD8 T cells from islets of remitted NOD had increased expressions of TOX and EOMES while with no difference in TCF-1, compared to their counterparts from paired pLN. In contrast, islet-infiltrating CD8 T cells of pre-diabetic NOD had decreased expressions of EOMES and TCF-1 but with no difference in TOX, compared to their pLN counterparts. Moreover, islet-infiltrating CD8 T cells of remitted NOD had higher median TCR entropy indicating a more diverse TCR repertoire than their counterparts from pre-diabetic NOD. These results suggest that anti-CD3 modulates the terminal differentiation of islet-infiltrating CD8 T cells. Tolerance is maintained by cells with stem-like and exhaustion features and a more diverse TCR repertoire.
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O’Rourke, John, Andrea Gomez-Donart, Caroline Weldon, and Zhaoping Liu. "Developing a novel multiplexed high throughput flow cytometry based immune assay to screen kinase modulators of primary T cell activation." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 131.7. http://dx.doi.org/10.4049/jimmunol.202.supp.131.7.
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Abstract Modulating TCR engagement and signaling using biologics, small molecules or genetic engineering is highly relevant to many therapeutic areas. TCR signal initiation is mediated by cytosolic tyrosine kinases, leading to signal amplification through a network of serine-threonine kinases. Genetic defects, mutations and other mechanisms leading to increased kinase activity and enhanced T cell activation (TCA) is involved in many autoimmune pathologies, making kinases attractive targets for the direct inhibition of TCA and treatment of autoimmune disease. The development of drugs and therapies regulating TCR activity require assays to profile T cell function and cell health. To address this need, we developed a novel multiplexed TCA assay based on high throughput flow cytometry technology with advanced computational algorithms for data analysis. The assay simultaneously measures T cell phenotype, time-dependent expression of T cell activation markers, cell proliferation and viability and quantitates secreted cytokines from a single 10 ml sample using a 96 or 384-well plate format. To illustrate the value of the TCA assay in drug discovery, we performed a phenotypic screen using a 152 kinase inhibitor (KI) small molecule library for their ability to inhibit human primary TCA. Using the Profile Mapping algorithm in our ForeCyt software, we integrated 11 TCA metrics to identify multiple inhibition pathways. The Profile Map tool was used to group KI based on their inhibition phenotypes, irrespective of their known targets. These results illustrate the use of Intellicyt’s technology to deliver solutions for drug and biologics discovery.
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Punt, J. A., J. L. Roberts, K. P. Kearse, and A. Singer. "Stoichiometry of the T cell antigen receptor (TCR) complex: each TCR/CD3 complex contains one TCR alpha, one TCR beta, and two CD3 epsilon chains." Journal of Experimental Medicine 180, no. 2 (August 1, 1994): 587–93. http://dx.doi.org/10.1084/jem.180.2.587.
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The stoichiometry of the subunits that comprise the T cell antigen receptor (TCR) complex is not completely known. In particular, it is uncertain whether TCR alpha and TCR beta proteins are present in the TCR complex as one or multiple heterodimeric pairs. In this study we have used mice transgenic for two different TCR alpha and two different TCR beta proteins to determine the number of TCR alpha and TCR beta chains in a single TCR complex. Individual thymocytes and splenic T cells from double TCR transgenic mice simultaneously expressed all four transgenic TCR proteins on their surfaces. Because the individual TCR alpha and individual TCR beta proteins were biochemically distinguishable, we were able to examine association among the transgenic TCR products. We found that each TCR alpha chain paired with each TCR beta chain, but that each TCR complex contained only one TCR alpha and one TCR beta protein. Furthermore, quantitative immunofluorescence revealed that T cells expressed twice as many CD3 epsilon as TCR beta proteins. These findings demonstrate that there are precisely one TCR alpha, one TCR beta, and two CD3 epsilon chains in each TCR/CD3 complex expressed on the surfaces of both thymocytes and mature T cells.
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Kinebuchi, M., A. Matsuura, T. Ogiu, and K. Kikuchi. "Deviated overexpression of TCR-beta, TCR-gamma, CD4, and CD8 on thymic lymphomas induced by 1-propyl-1-nitrosourea: destruction of the allelic exclusion of TCR-beta and expression of functional TCR-betagamma heterodimer on a lymphoma, cFTL53." Journal of Immunology 159, no. 2 (July 15, 1997): 748–56. http://dx.doi.org/10.4049/jimmunol.159.2.748.
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Abstract Thymic lymphomas (FTLs) induced by the chemical carcinogen 1-propyl-1-nitrosourea (PNU) in F344 rats showed deviated overexpression of TCR-beta, TCR-gamma, CD4, and CD8. Even though most FTLs were in the CD4+ CD8+ stage, all FTLs expressed TCR-beta mRNA with TCR-gamma mRNA, but without TCR-alpha mRNA or TCR-delta mRNA. One of the FTLs, cFTL53, expressed two kinds of TCR-beta mRNA and two kinds of TCR-gamma mRNA, but did not express any mRNA of TCR-alpha or TCR-delta. Both alleles of TCR-beta loci were rearranged on cFTL53. cDNA cloning and sequencing analysis showed that one TCR-gamma mRNA, Vgamma4-Jgamma1-Cgamma1, and both TCR-beta mRNA, Vbeta2-Dbeta2-Jbeta2.1 and Vbeta19-Dbeta2-Jbeta2.1-Cbeta2, on cFTL53 were in the productive form, while the other TCR-gamma mRNA, Vgamma1-Jgamma4-Cgamma4L, was not. Both TCR beta-chains and a TCR gamma-chain were expressed on cFTL53, making a novel set of TCR-betagamma heterodimer. Cross-linking of TCR-betagamma heterodimer on cFTL53 resulted in a calcium flux, indicating that TCR-betagamma works as a signal transduction receptor. Thus, there are four strange phenomena on FTLs; CD4 and CD8 are expressed without TCR-alphabeta or TCR-gammadelta, TCR-beta mRNA and TCR-gamma mRNA were expressed simultaneously without TCR-alpha and TCR-delta mRNA on FTLs, the allelic exclusion of TCR-beta was destroyed in cFTL53, and a novel set of functional TCR-betagamma heterodimer was expressed on cFTL53.
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Buer, Jan, Iannis Aifantis, James P. DiSanto, Hans Joerg Fehling, and Harald von Boehmer. "Role of Different T Cell Receptors in the Development of Pre–T Cells." Journal of Experimental Medicine 185, no. 9 (May 5, 1997): 1541–48. http://dx.doi.org/10.1084/jem.185.9.1541.
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The development of pre–T cells with productive TCR-β rearrangements can be mediated by each the pre–T cell receptor (pre-TCR), the TCR-αβ as well as the TCR-γδ, albeit by distinct mechanisms. Although the TCR-γδ affects CD4−8− precursor cells irrespective of their rearrangement status by TCR-β mechanisms not involving TCR-β selection, both the preTCR and the TCR-αβ select only cells with productive TCR-β genes for expansion and maturation. The TCR-αβ appears to be much less effective than the pre-TCR because of the paucity of TCR-α proteins in TCR-β–positive precursors since an early expressed transgenic TCR-αβ can largely substitute for the pre-TCR. Thus, the TCR-αβ can assume a role not only in the rescue from programmed cell death of CD4+8+ but also of CD4−8− thymocytes. In evolution this double function of the TCR-αβ may have been responsible for the maturation of αβ T cells before the advent of the pre–TCR-α chain.
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Yokosuka, Tadashi, Kan Takase, Misao Suzuki, Yohko Nakagawa, Shinsuke Taki, Hidemi Takahashi, Takehiko Fujisawa, Hisashi Arase та Takashi Saito. "Predominant Role of T Cell Receptor (TCR)-α Chain in Forming Preimmune TCR Repertoire Revealed by Clonal TCR Reconstitution System". Journal of Experimental Medicine 195, № 8 (15 квітня 2002): 991–1001. http://dx.doi.org/10.1084/jem.20010809.
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The CDR3 regions of T cell receptor (TCR)-α and -β chains play central roles in the recognition of antigen (Ag)-MHC complex. TCR repertoire is created on the basis of Ag recognition specificity by CDR3s. To analyze the potential spectrum of TCR-α and -β to exhibit Ag specificity and generate TCR repertoire, we established hundreds of TCR transfectants bearing a single TCR-α or -β chain derived from a cytotoxic T cell (CTL) clone, RT-1, specific for HIVgp160 peptide, and randomly picked up TCR-β or -α chains. Surprisingly, one-third of such TCR-β containing random CDR3β from naive T cells of normal mice could reconstitute the antigen-reactive TCR coupling with RT-1 TCR-α. A similar dominant function of TCR-α in forming Ag-specific TCR, though low-frequency, was obtained for lymphocytic choriomeningitis virus–specific TCR. Subsequently, we generated TCR-α and/or -β transgenic (Tg) mice specific for HIVgp160 peptide, and analyzed the TCR repertoire of Ag-specific CTLs. Similar to the results from TCR reconstitution, TCR-α Tg generated CTLs with heterogeneous TCR-β, whereas TCR-β Tg-induced CTLs bearing a single TCR-α. These findings of Ag recognition with minimum involvement of CDR3β expand our understanding regarding the flexibility of the spectrum of TCR and suggest a predominant role of TCR-α chain in determining the preimmune repertoire of Ag-specific TCR.
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Zaleski, J., G. Bator, and R. Jakubas. "Dielectric Properties and Characterisation of the Superionic Phase of [C(NH2)3]2SbCl5*[C(NH2)3]Cl (GHCA)." Zeitschrift für Naturforschung A 50, no. 9 (September 1, 1995): 888–92. http://dx.doi.org/10.1515/zna-1995-0916.
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GHCA undergoes four phase transitions at Tc1 = 402 K, Tc2 = 373 K, Tc3 = 162 K, and Tc4 = 146 K. Below Tc3 it possesses pyroelectric properties with the spontaneous polarization vector (Ps) in the ac plane and the maximum along the c axis equal to 8 μC/m2. Dielectric dispersion studies of GHCA show that the main dielectric dispersion connected probably with collective motions of chlorine ions is above 1GHz. For the phase transition at Tc2 to a superionic phase the thermal dilatation and electric conductivity were measured. The anomalies of the electric conductivity at Tc2 and Tc1 were observed with large values of σ(10-3 S/m) above Tc3. The guanidinium cations above Tc2, besides reorientational motions, undergo slow self diffusion.
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van Dongen, JJ, IL Wolvers-Tettero, F. Wassenaar, J. Borst, and P. van den Elsen. "Rearrangement and expression of T-cell receptor delta genes in T-cell acute lymphoblastic leukemias." Blood 74, no. 1 (July 1, 1989): 334–42. http://dx.doi.org/10.1182/blood.v74.1.334.334.
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Abstract We have analyzed T-cell receptor delta (TcR-delta) gene rearrangement and transcription in appropriately phenotyped mononuclear cells derived from 12 patients with T-cell acute lymphoblastic leukemia (T-ALL). The T-ALL cells were also analyzed for rearrangement and transcription of the T-cell receptor(TcR)-beta and gamma genes as well as for the presence of TcR-alpha gene transcripts. Four T-ALLs expressed TcR-gamma delta at the cell surface, while three expressed TcR-alpha beta. The other five T-ALLs did not express a TcR-CD3 complex on their cell membrane. The TcR-gamma delta + T-ALL had rearranged both TcR-delta gene alleles and contained mature 2.2 and 1.5 kb TcR-delta transcripts. In one case, immature 1.9 and 1.2 kb TcR-delta transcripts were also found. Furthermore they contained mature TcR-gamma mRNA, mature or immature TcR-beta mRNA, but no TcR-alpha mRNA. The three TcR-alpha beta + T-ALLs contained mature alpha and beta transcripts, but lacked TcR- delta transcripts as a result of deletion of both TcR-delta gene alleles. These data are in line with a mutually exclusive expression of TcR-alpha and -delta genes, which may be important to ensure the presence of only one type of TcR per T cell. One of the five CD3- T- ALLs had germline TcR-beta, gamma, and delta genes. The other four CD3- T-ALLs had rearranged their TcR-beta, gamma, and delta genes and contained immature 1.9 and 1.2 kb TcR-delta gene transcripts. Remarkably, one of these T-ALLs also contained TcR-alpha transcripts in addition to the immature TcR-delta transcripts, which was in line with the deletion of one TcR-delta gene allele and rearrangement of the other allele. This suggests that prevention of dual receptor expression may not only be regulated by the presence of germline TcR-alpha genes in TcR-gamma delta + cells or by deletion of both TcR-delta gene alleles in TcR-alpha beta + cells, but also via other regulation mechanisms. Finally, our data indicated that the combinatorial repertoire of the TcR-delta genes is limited, which has also been described for the TcR-gamma genes.
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van Dongen, JJ, IL Wolvers-Tettero, F. Wassenaar, J. Borst, and P. van den Elsen. "Rearrangement and expression of T-cell receptor delta genes in T-cell acute lymphoblastic leukemias." Blood 74, no. 1 (July 1, 1989): 334–42. http://dx.doi.org/10.1182/blood.v74.1.334.bloodjournal741334.
Full textAbstract:
We have analyzed T-cell receptor delta (TcR-delta) gene rearrangement and transcription in appropriately phenotyped mononuclear cells derived from 12 patients with T-cell acute lymphoblastic leukemia (T-ALL). The T-ALL cells were also analyzed for rearrangement and transcription of the T-cell receptor(TcR)-beta and gamma genes as well as for the presence of TcR-alpha gene transcripts. Four T-ALLs expressed TcR-gamma delta at the cell surface, while three expressed TcR-alpha beta. The other five T-ALLs did not express a TcR-CD3 complex on their cell membrane. The TcR-gamma delta + T-ALL had rearranged both TcR-delta gene alleles and contained mature 2.2 and 1.5 kb TcR-delta transcripts. In one case, immature 1.9 and 1.2 kb TcR-delta transcripts were also found. Furthermore they contained mature TcR-gamma mRNA, mature or immature TcR-beta mRNA, but no TcR-alpha mRNA. The three TcR-alpha beta + T-ALLs contained mature alpha and beta transcripts, but lacked TcR- delta transcripts as a result of deletion of both TcR-delta gene alleles. These data are in line with a mutually exclusive expression of TcR-alpha and -delta genes, which may be important to ensure the presence of only one type of TcR per T cell. One of the five CD3- T- ALLs had germline TcR-beta, gamma, and delta genes. The other four CD3- T-ALLs had rearranged their TcR-beta, gamma, and delta genes and contained immature 1.9 and 1.2 kb TcR-delta gene transcripts. Remarkably, one of these T-ALLs also contained TcR-alpha transcripts in addition to the immature TcR-delta transcripts, which was in line with the deletion of one TcR-delta gene allele and rearrangement of the other allele. This suggests that prevention of dual receptor expression may not only be regulated by the presence of germline TcR-alpha genes in TcR-gamma delta + cells or by deletion of both TcR-delta gene alleles in TcR-alpha beta + cells, but also via other regulation mechanisms. Finally, our data indicated that the combinatorial repertoire of the TcR-delta genes is limited, which has also been described for the TcR-gamma genes.
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Silva, Paulo Igor Barbosa e., Maria Zuleide de Negreiros, Karidja Kalliany Carlos de Freitas Moura, Francisco Cláudio Lopes de Freitas, Glauber Henrique de Sousa Nunes, Paulo Sérgio Lima e. Silva, and Leilson Costa Grangeiro. "Crescimento de pimentão em diferentes arranjos espaciais." Pesquisa Agropecuária Brasileira 45, no. 2 (February 2010): 132–39. http://dx.doi.org/10.1590/s0100-204x2010000200003.
Full textAbstract:
O objetivo deste trabalho foi avaliar o crescimento do pimentão cv. Atlantis sob diferentes arranjos espaciais. Foram avaliados três arranjos de espaçamentos entre fileiras duplas e fileiras simples de plantio (1,5x0,5, 1,6x0,4 e 1,7x0,3 m), e quatro espaçamentos entre plantas nas fileiras (0,2, 0,3, 0,4 e 0,5 m), combinados em esquema fatorial. Utilizou-se o delineamento de blocos ao acaso, com três repetições e parcelas subdivididas no tempo. A avaliação de crescimento foi realizada em nove épocas espaçadas em 14 dias, com a primeira avaliação realizada 14 dias após o transplantio (DAT). Até os 126 DAT, foram avaliados: área foliar (AF); índice de área foliar (IAF); massas secas de folhas (MSF), do caule (MSC), de frutos (MSFr) e do total da parte aérea (MST); taxa de crescimento absoluto (TCA), assimilatória líquida (TAL) e de crescimento relativo (TCR); e as razões de área foliar (RAF) e de massa foliar (RMF). As alterações em AF, TCR, RMF e RAF foram independentes do espaçamento entre fileiras que, no entanto, influenciou MSF, MSC, MSFr e MST, IAF e TCA. O aumento do espaçamento entre plantas reduz o IAF e a RAF e aumenta a AF, MSF, MSC, MSFr, MST, TCA e TAL, mas não influencia a TCR e RMF.
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Makazlieva, Tanja, Olivija Vaskova, Toni Tripunoski, Sinisha Stojanoski, Nevena Manevska, Zlatko Jakovski, Sasho Risteski, Hilda Jovanovic, and Aleksandar Eftimov. "Thyroid Stimulating Hormone Receptor Transcripts in Correlation with Clinical Parameters in Thyroid Carcinoma Patients." Open Access Macedonian Journal of Medical Sciences 8, A (September 23, 2020): 866–72. http://dx.doi.org/10.3889/oamjms.2020.5099.
Full textAbstract:
BACKGROUND: Differentiated thyroid carcinomas (DTC) preserve expression of thyroid stimulating hormone receptor (TSHR).
 AIM: The aim of our study was to evaluate the expression of mRNA-TSHR in peripheral blood of DTC patients, then to correlate the expression with clinical features: Serum thyroglobulin (sTg) value, initial staging and findings from the whole body scan (WBS), neck ultrasound (US), and total received dose of radioiodine therapy.
 MATERIALS AND METHODS: Forty patients were divided into three groups according to the treatment response: Patients with incomplete structural response (TCs), incomplete biochemical response (TCb), and excellent responders (TCr). Total RNA was isolated from peripheral blood and used for two-step reverse transcriptase-PCR with appropriate primers. Relative quantification using the ΔCt and 2–ΔΔCt and method was applied. sTg levels were evaluated with chemiluminescent assay. The statistical analysis was performed with Spearman Rank Order Correlation.
 RESULTS: We found that TCs patients expressed mRNA-TSHR by a 5.37-fold higher level than TCr patients, TCb patients expressed TSHR by an 8.88-fold higher level than TCr patients. A significant negative correlation was detected between sTg and ΔCt (CtTSHR - CtGAPDH) value (R = −0.475; p < 0.05), and between WBS/US findings and ΔCt (R= −0.321; p < 0.05).
 CONCLUSION: Our data revealed higher expression of mRNA-TSHR in peripheral blood of TCs and TCb compared to TCr patients and analysis revealed a significant correlation between mRNA-TSHR and sTg and US/WBS findings. Further studies with larger number of subjects and absolute quantification are needed for understanding the real meaning of mRNA-TSHR as a biomarker in DTC.
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Cerwenka, Adelheid, Laura L. Carter, Joyce B. Reome, Susan L. Swain, and Richard W. Dutton. "In Vivo Persistence of CD8 Polarized T Cell Subsets Producing Type 1 or Type 2 Cytokines." Journal of Immunology 161, no. 1 (July 1, 1998): 97–105. http://dx.doi.org/10.4049/jimmunol.161.1.97.
Full textAbstract:
Abstract Naive CD8 T cells can be polarized into effectors producing the type 1 cytokines IFN-γ and IL-2 or the type 2 cytokines IL-4, IL-5, and IL-10, respectively. To study whether the polarized cytokine phenotype of the effectors is stable, we generated highly cytotoxic hemagglutinin (HA) peptide-specific CD8 Tc1 and Tc2 (cytotoxic CD8 T cells producing type 1 or type 2 cytokines) effectors from Clone-4 TCR-transgenic mice, which were adoptively transferred into syngeneic adult thymectomized irradiated and bone marrow-reconstituted recipients. The highly activated blast-size, CD25+ Tc1 and Tc2 effectors gave rise to homogeneous resting CD25−CD44highLy6Chigh Ag-specific populations, which persisted for at least 13 wk after adoptive transfer. These memory CD8 T cells, recovered 13 wk after transfer of Tc1 or Tc2 effectors, still produced either the type 1 or type 2 cytokines, i.e., IFN-γ, or IL-4 and IL-5, respectively, upon restimulation with APCs loaded with the HA peptide, but not in the absence of Ag. The amounts of IL-2 detected in the supernatants of Tc1 and Tc2 memory populations were comparable to that in memory CD4 cells, and both Tc1 and Tc2 memory cells became cytotoxic upon restimulation. Thus, cytokine-polarized CD8 memory T cells are a source of a variety of cytokines, which were classically considered helper cytokines, opening new perspectives on their function as regulatory cells in an immune response.