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1
Gunes, Emine Gulsen, Hadas Lewinsky, Domenico Viola, Enrico Caserta, Michael Rosenzweig, Myo Htut, James F. Sanchez, et al. "CD84: A Potential Novel Therapeutic Target in Multiple Myeloma." Blood 132, Supplement 1 (November 29, 2018): 1924. http://dx.doi.org/10.1182/blood-2018-99-119655.
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Abstract Introduction: Multiple Myeloma (MM) cell survival strictly depends on the interaction with multiple cell types in the bone marrow (BM), collectively referred to as the MM microenvironment (MM-ME). CD84 (SLAMF5) belongs to the signaling lymphocyte activation molecule family of immunoreceptors; previous data from our group have shown that CD84 mediates malignant B cells and their ME (Marom et al. 2017); however, its role within the MM-ME has not yet been investigated. Results: Using the MMRF CoMMpass IA9 dataset, we found that CD84 mRNA expression is low or absent in CD138+MM cells isolated from 660 newly diagnosed patients. In agreement with these data, flow analysis showed an absence of CD84 expression in all MM cell lines tested (n=9) and minimal surface expression (5.5-13%) in primary cells (n=3). However, a significantly higher expression of CD84 was detected on the surface of BM and peripheral blood (PB) monocytic fractions (CD14+) (76-97%) compared to that of matched CD14 negative fractions (2-9%) obtained from 16 different MM patients (p<0.001). Since it was recently reported that CD14+ monocytic myeloid derived suppressor cells (Mo-MDSCs) play a pivotal role in supporting MM growth by creating an immunosuppressive ME, we investigated CD84 expression in this population. Using primary PB (n=9) and BM (n=3) samples obtained from MM patients with active disease, we found that the Mo-MDSC population is significantly over-represented (0.34-2.88%) in MM patients compared to the PB from healthy donors (n=7) (0.04-0.45%) (p<0.05) and that CD84 is also significantly up-regulated in this population in MM patients (43-92%) compared to healthy donors (7-21%) (p<0.001). Next, to understand whether the expansion of Mo-MDSC and associated CD84 up-regulation is directly dependent on the MM cells, we investigated Mo-MDSC expansion and CD84 expression in two different MM mouse models. Specifically, 5TGM1 murine MM cells were IV injected into syngeneic immune-competent KaLwRijHsd mice (n=7), and human MM.1S cells were IV injected into immune-deficient NSG mice (n=10). Our data show that MM progression leads to significant Mo-MDSC expansion (p<0.0001) and a subsequent increase in CD84 levels (p<0.05) on this population in both mouse models. Since T cell checkpoint inhibitors PD-1/PD-L1 are tumor immune escape receptors that play a pivotal role in supporting an immunosuppressive MM-ME, we also investigated the expression of PD-L1 on the CD14+ fraction in MM patients. BM-CD14+ cells (n=3) were compared with matched CD14 negative cells. We found that the CD14+ fraction had a higher PD-L1 expression in the BM of MM patients compared to the CD14 negative fraction (60-96% versus 3-8%). Hence, we investigated whether CD84-mediated cell-cell contact may increase the level of PD-L1 expression on Mo-MDSCs and whether MM cells can regulate CD84 and PD-L1 expression on CD14+ cells. Co-culture assays were performed using several human MM cell lines (MM1S, U266 and KMS11) with PB CD14+ cells derived from healthy donors (n=3). Our data show a 1.9-fold increase from the basal level of CD84 (27±16% to 50±9.4%) and a 2.9-fold increase from the basal level of PD-L1 (18±8.5% to 52.3±5.7%). Our recently generated mouse anti-human CD84 blocking antibody (Marom et al. 2017) was used to determine whether CD84 direct targeting can affect MM-induced CD84 and PD-L1 expression on the surface of CD14+cells. Co-culture experiments show that targeting CD84 lowered CD84 (1.6-fold decrease) and PD-L1 expression (1.8-fold decrease) on a CD14+ population co-cultured with MM cells. Moreover, when T cells were included in the co-culture experiments, we observed reduced expression of exhaustion markers PD-1 (1.1-fold decrease) and CTLA4 (1.4-fold decrease) in the presence of the CD84 blocking antibody. Conclusion: We show here that CD84 is expressed on Mo-MDSCs in MM and that the expansion of this myeloid population is strictly associated with MM progression. Disruption of CD84 contacts with a blocking antibody decreases the expression of PD-L1 on CD14+ cells and exhaustion markers on T cells. Thus, our results reveal a novel role for CD84 in regulating PD-L1 in the MM-ME and provides the scientific rationale to investigate whether targeting CD84 expression on Mo-MDSCs can restore T cell functions. To further confirm the role of CD84 regulating T cell activity and Mo-MDSC, in vivo mouse studies are ongoing and results will be presented at the meeting. Disclosures Rosenzweig: Celgene: Speakers Bureau. Krishnan:Sutro: Speakers Bureau; Onyx: Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Equity Ownership, Speakers Bureau; Takeda: Speakers Bureau.
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Schuhmann, Michael K., Guido Stoll, Michael Bieber, Timo Vögtle, Sebastian Hofmann, Vanessa Klaus, Peter Kraft, et al. "CD84 Links T Cell and Platelet Activity in Cerebral Thrombo-Inflammation in Acute Stroke." Circulation Research 127, no. 8 (September 25, 2020): 1023–35. http://dx.doi.org/10.1161/circresaha.120.316655.
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Rationale: Ischemic stroke is a leading cause of morbidity and mortality worldwide. Recanalization of the occluded vessel is essential but not sufficient to guarantee brain salvage. Experimental and clinical data suggest that infarcts often develop further due to a thromboinflammatory process critically involving platelets and T cells, but the underlying mechanisms are unknown. Objective: We aimed to determine the role of CD (cluster of differentiation)-84 in acute ischemic stroke after recanalization and to dissect the underlying molecular thromboinflammatory mechanisms. Methods and Results: Here, we show that mice lacking CD84—a homophilic immunoreceptor of the SLAM (signaling lymphocyte activation molecule) family—on either platelets or T cells displayed reduced cerebral CD4 + T-cell infiltration and thrombotic activity following experimental stroke resulting in reduced neurological damage. In vitro, platelet-derived soluble CD84 enhanced motility of wild-type but not of Cd84 −/− CD4 + T cells suggesting homophilic CD84 interactions to drive this process. Clinically, human arterial blood directly sampled from the ischemic cerebral circulation indicated local shedding of platelet CD84. Moreover, high platelet CD84 expression levels were associated with poor outcome in patients with stroke. Conclusions: These results establish CD84 as a critical pathogenic effector and thus a potential pharmacological target in ischemic stroke.
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de la Fuente, Miguel Angel, Pilar Pizcueta, Marga Nadal, Jaime Bosch, and Pablo Engel. "CD84 Leukocyte Antigen Is a New Member of the Ig Superfamily." Blood 90, no. 6 (September 15, 1997): 2398–405. http://dx.doi.org/10.1182/blood.v90.6.2398.
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Abstract cDNA isolated from a human B-cell line Raji library was analyzed and shown to encode the full-length cDNA sequence of a novel cell-surface glycoprotein, initially termed HLy9-β. The predicted mature 307-amino acid protein was composed of two extracellular Ig-like domains, a hydrophobic transmembrane region, and an 83-amino acid cytoplasmic domain. The extracellular Ig-like domains presented structural and sequence homology with a group of members of the Ig superfamily that included CD2, CD48, CD58, and Ly9. Northern blot analysis showed that the expression of HLy9-β was predominantly restricted to hematopoietic tissues. Chromosome localization studies mapped the HLy9-β gene to chromosome 1q24, where other members of this Ig superfamily (CD48 and HumLy9) have been mapped. CD84 monoclonal antibodies (MoAbs) were shown to react with cells transfected with the cloned cDNA. These MoAbs were further used to show that CD84 is expressed as a single chain cell-surface glycoprotein of Mr 64,000 to 82,000, which was highly glycosylated. CD84 had a unique pattern of expression, being found predominantly on lymphocytes and monocytes. Thus, the glycoprotein HLy9-β is recognized by MoAbs previously clustered as CD84 and represents a newly identified member of the Ig superfamily that may play a significant role in leukocyte activation.
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de la Fuente, Miguel Angel, Pilar Pizcueta, Marga Nadal, Jaime Bosch, and Pablo Engel. "CD84 Leukocyte Antigen Is a New Member of the Ig Superfamily." Blood 90, no. 6 (September 15, 1997): 2398–405. http://dx.doi.org/10.1182/blood.v90.6.2398.2398_2398_2405.
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cDNA isolated from a human B-cell line Raji library was analyzed and shown to encode the full-length cDNA sequence of a novel cell-surface glycoprotein, initially termed HLy9-β. The predicted mature 307-amino acid protein was composed of two extracellular Ig-like domains, a hydrophobic transmembrane region, and an 83-amino acid cytoplasmic domain. The extracellular Ig-like domains presented structural and sequence homology with a group of members of the Ig superfamily that included CD2, CD48, CD58, and Ly9. Northern blot analysis showed that the expression of HLy9-β was predominantly restricted to hematopoietic tissues. Chromosome localization studies mapped the HLy9-β gene to chromosome 1q24, where other members of this Ig superfamily (CD48 and HumLy9) have been mapped. CD84 monoclonal antibodies (MoAbs) were shown to react with cells transfected with the cloned cDNA. These MoAbs were further used to show that CD84 is expressed as a single chain cell-surface glycoprotein of Mr 64,000 to 82,000, which was highly glycosylated. CD84 had a unique pattern of expression, being found predominantly on lymphocytes and monocytes. Thus, the glycoprotein HLy9-β is recognized by MoAbs previously clustered as CD84 and represents a newly identified member of the Ig superfamily that may play a significant role in leukocyte activation.
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Distler, Eva, Anna Jürchott, Abdo Konur, Astrid Schneider, Eva M. Wagner, Christoph Huber, Ralf G. Meyer, and Wolfgang Herr. "The CD38-Positive and CD38-Negative Subsets of CD34(high)-Positive Primary Acute Myeloid Leukemia Blasts Differ Considerably in the Expression of Immune Recognition Molecules." Blood 112, no. 11 (November 16, 2008): 2936. http://dx.doi.org/10.1182/blood.v112.11.2936.2936.
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Abstract Acute myeloid leukemia (AML) is thought to arise from a rare putative ‘leukemic stem cell’ that is capable of self-renewal and formation of leukemic blasts. Serial xenotransplantation studies in immunodeficient mice have shown that this leukemia-initiating cell resides at very low numbers within CD34(high)-positive CD38-negative AML cells. Thus, immunotherapeutic approaches successfully eradicating this cell compartment should result in cure from disease. The objective of our study was to characterize the immune phenotype of the CD38-negative and CD38-positive subsets of primary CD34(high)-positive AML blasts ex vivo. We obtained therapeutic leukapheresis products from 17 AML patients of FAB M0-M5 subtypes with white blood cell counts exceeding 10^11/L at primary diagnosis. These products were used to purify CD34-positive cells by immunomagnetic microbeads. CD34(high)-expressing cells were subsequently sorted by flow cytometry into CD38-negative and CD38-positive subsets, respectively. Both fractions were then phenotyped with fluorochrome-conjugated monoclonal antibodies for expression of surface markers previously described to differ between leukemic blasts and stem cells, i.e. CD71 (transferrin receptor), CD90 (Thy-1), CD117 (c-kit receptor), CD123 (IL3Ralpha), CD44, and CD11c. We also included markers relevant for recognition by natural killer cells and T cells, namely HLA class I, HLA-DR, CD40, CD54 (ICAM-1), CD58 (LFA-3), CD80 (B7.1), and CD86 (B7.2), as well as the lineage markers CD2, CD3, CD4, CD7, CD8, CD10, CD14, CD19, CD20, and CD56. Our results demonstrated that the CD38-positive and CD38-negative subsets of CD34(high)-positive AML blasts differed considerably in the expression of CD58, CD71, CD86, CD117, and HLA class I. Although these markers were detected on both subsets, the mean fluorescence intensity (MFI) values were lower in the CD38-negative compartment compared to the CD38-positive counterpart (medians: CD58, 1335 versus 1933; CD71, 657 versus 811; CD86, 746 versus 753; CD117, 490 versus 758; HLA class I, 4431 versus 6000). We compared the MFI values of both cell subsets with the Wilcoxon signed-rank test. P-values below 5% were detected for CD58 (p=0.005), CD71 (p=0.003), CD86 (p=0.041), CD117 (p=0.009), and HLA class I (p=0.011), respectively. The CD38-positive and CD38-negative subsets showed comparable intense staining for CD11c, CD44, CD54, CD123, and HLA-DR. In contrast, CD90, CD80, CD40, and the lineage markers were negative in both fractions. We concluded from these results that primary CD34(high)-positive CD38-negative AML blasts containing small numbers of leukemia-initiating cells expressed overall lower levels of the immune recognition molecules CD58 (LFA-3), CD86 (B7.2), and HLA class I compared to their CD38-positive counterparts. However, all CD34(high)-positive CD38-negative AML cells showed detectable HLA class I expression on the cell surface, making them accessible to T-cell based immunotherapies. In line with previous data, CD71 (transferrin receptor) and CD117 (c-kit receptor) were observed at reduced levels on CD34(high)-positive CD38-negative AML cells. Ongoing functional studies explore if the CD38-negative and CD38-positive subsets of CD34(high)-positive AML blasts differ in the immunogenicity for leukemia-reactive CD4 and CD8 T cells, both in vitro as well as in immunodeficient mice in vivo.
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Marom, A., A. F. Barak, M. P. Kramer, H. Lewinsky, I. Binsky-Ehrenreich, S. Cohen, A. Tsitsou-Kampeli, et al. "CD84 mediates CLL-microenvironment interactions." Oncogene 36, no. 5 (July 25, 2016): 628–38. http://dx.doi.org/10.1038/onc.2016.238.
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Nanda, Nisha, Patrick Andre, Ming Bao, Karl Clauser, Francis Deguzman, Duncan Howie, Pamela B. Conley, Cox Terhorst, and David R. Phillips. "Platelet aggregation induces platelet aggregate stability via SLAM family receptor signaling." Blood 106, no. 9 (November 1, 2005): 3028–34. http://dx.doi.org/10.1182/blood-2005-01-0333.
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AbstractPlatelet aggregation is a dynamic entity, capable of directing its own growth and stability via the activation of signaling cascades that lead to the expression and secretion of various secondary agonists. Here we show that the signaling pathways triggered during platelet aggregation include an intrinsic pro-thrombotic activity mediated by 2 homophilic adhesion molecules, CD84 and CD150 (SLAM [signaling lymphocyte activation molecule]), which are tyrosine phosphorylated in a platelet aggregation–dependent fashion. The 2 CD84/SLAM adapter proteins, SAP (SLAM-associated protein) and EAT-2 (EWS-activated transcript-2), were found in platelets; only SAP, however, was found to immunoprecipitate with tyrosine-phosphorylated SLAM. The immobilized extracellular domain of CD84 promoted microaggregate formation, while SAP-deficient platelets demonstrated defective spreading on immobilized CD84, demonstrating a functional role in platelets for SLAM family interactions. Finally, analysis of SLAM-deficient mice revealed an overall defect in platelet aggregation in vitro and a delayed arterial thrombotic process in vivo. The data indicate that signaling of the adhesion molecules in the SLAM family, activated by proximity during aggregation, further stabilize platelet-platelet interactions in thrombosis.
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Caux, C., B. Vanbervliet, C. Massacrier, I. Durand, and J. Banchereau. "Interleukin-3 cooperates with tumor necrosis factor alpha for the development of human dendritic/Langerhans cells from cord blood CD34+ hematopoietic progenitor cells." Blood 87, no. 6 (March 15, 1996): 2376–85. http://dx.doi.org/10.1182/blood.v87.6.2376.bloodjournal8762376.
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We have previously shown that tumor necrosis factor (TNF)alpha strongly potentiates the granulocyte-macrophage colony-stimulating factor (GM- CSF)/interleukin (IL)-3-dependent proliferation of CD34+ hematopoietic progenitor cells (HPC) through the recruitment of early progenitors with high proliferative potential. Furthermore, the combination of GM- CSF and TNFalpha allows the generation of large numbers of dendritic/Langerhans cells (D-Lc). Herein, we analyzed whether IL-3, when combined to TNFalpha would, as does GM-CSF, allow the generation of CD1a+ D-Lc. Accordingly, cultures of cord blood CD34+ HPC with IL-3 + TNFalpha yielded 20% to 60% CD14+ cells and 11% to 17% CD1a+ cells, while IL-3 alone did not generate significant numbers of CD1a+ cells. Although the percentage of CD1a+ cells detected in IL3 + TNFalpha was lower than that observed in GM-CSF + TNFalpha (42% to 78%), the strong growth induced by IL-3 + TNFalpha generated as many CD1a+ cells as did GM-CSF + TNFalpha. The CD14+ and CD1a+ cells generated with IL-3 + TNFalpha are similar to CD14+ and CD1a+ cells generated in GM-CSF alone and GM-CSF + TNFalpha, respectively. CD1a+ cells differed from CD14+ cells by (1) dendritic morphology, (2) higher expression of CD1a, CD1c, CD4, CD40, adhesion molecules (CD11c, CD54, CD58), major histocompatibility complex (MHC) class II molecules and CD28 ligands (CD80 and CD86), (3) lack of Fc receptor FcgammaRI (CD64) and complement receptor CR1 (CD35) expression, and (4) stronger induction of allogeneic T-cell proliferation. Thus, in combination with TNFalpha, IL-3 is as potent as GM-CSF for the generation of CD1a+ D-Lc from cord blood CD34+ HPC. The dendritic cell inducing ability of IL-3 may explain why mice with inactivated GM-CSF gene display dendritic cells.
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Sayós, Joan, Margarita Martı́n, Alice Chen, Marı́a Simarro, Duncan Howie, Massimo Morra, Pablo Engel, and Cox Terhorst. "Cell surface receptors Ly-9 and CD84 recruit the X-linked lymphoproliferative disease gene product SAP." Blood 97, no. 12 (June 15, 2001): 3867–74. http://dx.doi.org/10.1182/blood.v97.12.3867.
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X-linked lymphoproliferative disease (XLP) is a rare immune disorder commonly triggered by infection with Epstein-Barr virus. Major disease manifestations include fatal acute infectious mononucleosis, B-cell lymphoma, and progressive dys-gammaglobulinemia. SAP/SH2D1A, the product of the gene mutated in XLP, is a small protein that comprises a single SH2 domain and a short tail of 26 amino acids. SAP binds to a specific motif in the cytoplasmic tails of the cell surface receptors SLAM and 2B4, where it blocks recruitment of the phosphatase SHP-2. Here it is reported that Ly-9 and CD84, 2 related glycoproteins differentially expressed on hematopoietic cells, also recruit SAP. Interactions between SAP and Ly-9 or CD84 were analyzed using a novel yeast 2-hybrid system, by COS cell transfections and in lymphoid cells. Recruitment of SAP is most efficient when the specific tyrosine residues in the cytoplasmic tails of Ly-9 or CD84 are phosphorylated. It is concluded that in activated T cells, the SAP protein binds to and regulates signal transduction events initiated through the engagement of SLAM, 2B4, CD84, and Ly-9. This suggests that combinations of dysfunctional signaling pathways initiated by these 4 cell surface receptors may cause the complex phenotypes of XLP.
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Lukic, Aleksandra, Vesna Danilovic, and Renata Petrovic. "Comparative immunohistochemical and quantitative analysis of inflammatory cells in symptomatic and asymptomatic chronic periapical lesions." Vojnosanitetski pregled 65, no. 6 (2008): 435–40. http://dx.doi.org/10.2298/vsp0806435l.
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Background/Aim. It has been demonstrated that lymphocytes, plasma cells, macrophages and neutrophil granulocytes represent the predominant cells of the inflammatory lesion of the dental granulomas. Other cells, such as mast cells, eosinophils, dendritic cells comprise minor, but functionally important cell populations. Most of the data considering cells that take part in these processes have been derived from immunohistological studies. This study was undertaken with the aim to determine the phenotype profile of inflammatory cells of dental granulomas using immunohistochemical method in order to study the differences of their quantitative properties and distribution between symptomatic and asymptomatic lesions. Methods. The material for the analysis originated from 42 individuals with clinic and radiographic diagnosis of chronic periapical lesions. The tissue was take either during the periradicular surgery, or tooth extraction. Cryostat tissue sections were stained using the alkaline phosphatase-antialkaline phosphatase assay (APAAP). This method is highly valid and sensitive using a panel of specific monoclonal antibodies: CD3, CD4, CD8, CD19, CD38, CD14, CD1a, CD83, CD80, CD86, CD45 and CD123. Results. The composition of the cell population revealed that there was no homogenous and site-specific pattern of the distribution of inflammatory cells. The results of our investigation revealed that the majority of inflammatory cells comprised lymphocytes and plasma cells, followed by subpopulations CD4+, CD8+ and CD14+ cells. Much lower in number were CD80+, CD86+ and CD83+ and CD1a+ cells. There were no statistically significant differences in mean values of inflammatory cells number between symptomatic and asymptomatic lesions, with the exception of CD86+ cells, the number of which was statistically higher in symptomatic lesions. Conclusion. Inflammatory infiltrate cells in dental granulomas are dominated by T- and Blymphocytes. It points out the complexity of immunopathogenic events in imitiating and progressing of dental granulomas that involve mechanisms of both cellular and humoral immunity. Regarding the quantitative presence of immunocompetent cells in symptomatic and asymptomatic lesions no statistically significant difference was determined unless in mature dendritic cells present in symptomatic lesions.
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Zaiss, Matthias, Christian Hirtreiter, Michael Rehli, Annegret Rehm, Leoni A. Kunz-Schughart, Reinhard Andreesen, and Burkhard Hennemann. "CD84 expression on human hematopoietic progenitor cells." Experimental Hematology 31, no. 9 (September 2003): 798–805. http://dx.doi.org/10.1016/s0301-472x(03)00187-5.
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Saito, Yoshinobu, Makoto Hirokawa, Kunie Saito, Yong-Mei Guo, Miwa Hebiguchi, Yoshinari Kawabata, Atsushi Komatsuda, Naoto Takahashi, Junsuke Yamashita, and Ken-ichi Sawada. "Phagocytosis of Co-Developing Neutrophil Progenitors by Dendritic Cells in Culture with Granulocyte-Colony Stimulating-Factor and Tumor Necrosis Factor-α: Induction of T Regulatory Cells by Co-Developing Dendritic Cells." Blood 108, no. 11 (November 16, 2006): 1720. http://dx.doi.org/10.1182/blood.v108.11.1720.1720.
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Abstract Tumor necrosis factor-α (TNF-α) has been shown to sustain differentiation and proliferation of CD34+ cells toward dendritic cells (DCs). Granulocyte-colony stimulating-factor (G-CSF) sustains differentiation and proliferation of CD34+ cells toward neutrophils and has been shown to have immune-modulatory effects. We hypothesized that co-stimulation of G-CSF and TNF-α generate neutrophil progenitors and DCs together from human CD34+ cells and that interaction of these cells may provide physiological and/or a pathological roles in modulating immune response. Methods. Highly purified human CD34+ cells were cultured with G-CSF, with or without TNF-α and induced to undergo differentiation toward neutrophils. We enumerated neutrophil progenitors using the specific marker CD15, and DCs using CD4, CD11c, CD80, CD83, CD86, and CD123. The character and roles of co-developing DCs in the presence of TNF-α were analyzed by fluorescence-activated cell sorter, enzyme immunohistochemistry, confocal microscopy and mixed lymphocyte reaction (MLR). Cytokine production was assessed using a cytometric bead array system. T reguratory cells (Treg) were defined as CD4+CD25+ cells and the cells expressing Fox P3. Results. When CD34+ cells were cultured for 7 days in the presence of G-CSF, the generated cells predominantly expressed CD15 (71.8±0.6%), while rarely expressing CD11c (8.0±2.2%), CD80 (1.4±1.0%), CD83 (2.9±0.5%), or CD86 (5.6±2.9%). The addition of TNF-α significantly decreased the number of cells expressing CD15 (3.5±2.1%), but did not affect the number of total cells. In the presence of TNF-α, the generated cells expressed major histocompatibility complex (MHC) class I (99.5%) plus MHC class II (90.2%). A substantial number of cells became positive for CD11c (70.9±5.3%), and even co-stimulatory molecules such as CD80 (8.0±2.7%), CD83 (15.9±3.0%), and CD86 (39.6±3.2%). Immature CD11c+ DCs were physically associated with apoptotic and CD15+ cells, and capable of endocytosing CD15+ cells. Most of the CD11c+ cells did not co-express the G-CSF receptor, but expressed CD4 and CD123. About one half of CD11c+ cells co-expressed CD86. The DCs generated by TNF-α and G-CSF facilitated alloreactive T cell proliferation in the same extent, although cytokine production from activated T cells were low. Primary MLR facilitated the proliferation of CD4+CD25+ cells and Fox P3+ Treg. The CD4+ CD25+ T cells suppressed secondary MLR, whereas CD4+ CD25− T cells enhanced secondary MLR. Conclusions. This is the first report showing that. the non-neutrophilic cells with typical feature of DCs are co-generated from human CD34+ cells during neutrophil differentiation by G-CSF in the presence of TNF-α. The CD4+ CD11c+ CD123+ DCs physically associate with and phagocytoses developing or dying immature neutrophilic cells. The generated DCs promoted the proliferation of Treg that suppressed secondary MLR. Therefore, it may be conceivable that DCs with phagocytic activity during the development in bone marrow may play a crucial role in the maintenance of tolerance for self-substances derived from hematopoietic progenitor cells.
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Nauta, Alma J., Ellie Lurvink, Alwine B. Kruisselbrink, Roelof Willemze, and Willem E. Fibbe. "Mesenchymal Stem Cells Inhibit Generation and Function of Both Monocyte-Derived and CD34-Derived Dendritic Cells." Blood 106, no. 11 (November 16, 2005): 593. http://dx.doi.org/10.1182/blood.v106.11.593.593.
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Abstract Mesenchymal stem cells (MSCs) have been demonstrated to exert profound immunosuppressive properties on T cell proliferation. However, their effect on the initiators of the immune response, the dendritic cells (DCs), are relatively unknown. In the present study, the effects of MSCs on the differentiation and function of both monocyte-derived DCs and CD34+-derived DCs were investigated. Monocytes (CD1a-CD14+) were obtained from PB and were cultured with IL-4 and GM-CSF to induce differentiation into CD14-CD1a+ immature DCs. CD34+ hematopoietic progenitor cells were isolated from umbilical cord blood samples and cultured in the presence of GM-CSF, TNF-a, and SCF to generate Langerhans cells, which differentiate directly into CD1a+ DCs, and dermal/interstitial DCs, which differentiate via an intermediate CD14+CD1a- phenotype into CD14-CD1a+ DCs. MSCs were generated from fetal lung tissue as reported previously (Exp. Hematol.2002; 30: 870–878). The phenotype (CD1a, CD14, CD80, CD86, CD83, HLA-DR, CD40) of the cells was analyzed by flow cytometry; cytokine production (IL-12, TNF-α) was examined by enzyme-linked immunosorbent assay (ELISA) and T cell stimulatory capacity was determined by a mixed lymphocyte reaction (MLR). The presence of MSCs during the complete differentiation period completely prevented the generation of immature DCs (CD1a+CD14-) from monocytes in a dose-dependent manner. MSCs in the upper wells of a transwell culture system inhibited the differentiation of monocytes in the lower wells, indicating that the suppressive effect of MSCs was mediated via soluble factors. The inhibitory effect of MSCs on the differentiation of DCs was partially prevented by the addition of neutralizing antibodies to IL-6 and M-CSF, indicating the involvement of these cytokines. Upon removal of MSCs cultured in a transwell after 48h, differentiation of monocytes towards DCs was restored, indicating that the suppressive effect of MSCs was reversible. DCs generated in the presence of MSCs were unresponsive to signals inducing maturation (CD40 ligand, lipopolysaccharide), as demonstrated by the absence of CD83, CD80, CD86 and HLA-DR upregulation and the decreased production of the inflammatory cytokines TNF-α (76%) and IL-12 (79%). In addition, the T cell stimulatory capacity of mature DCs generated in the presence of MSCs was strongly reduced. MSCs also inhibited the generation of DCs from CD34+ progenitor cells by blocking the differentiation of CD14+CD1a- precursors into dermal/interstitial DCs, without affecting the generation of CD1a+ Langerhans cells. The inhibitory effect of MSCs on CD34+ cell differentiation was dose-dependent and resulted in both phenotypical and functional modifications, as demonstrated by a reduced expression of costimulatory molecules (CD80, CD86) and CD83, and hampered capacity to stimulate naïve T-cell proliferation (50,112 ± 1,305 cpm versus 20,412 ± 1,593 cpm). Taken together, these data demonstrate that MSCs, next to the anti-proliferative effect on T cells, have a profound inhibitory effect on the generation and function of both monocyte- and CD34+-derived DCs, indicating that MSCs are able to modulate immune responses at multiple levels.
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van Loenen, Marleen M., Renate S. Hagedoorn, Roelof Willemze, J. H. Frederik Falkenburg, and Mirjam H. M. Heemskerk. "Extracellular Domains of CD8a and β Subunits Are Required and Sufficient for HLA Class I Restricted Helper Activity of TCR-Engineered CD4+ T Cells." Blood 114, no. 22 (November 20, 2009): 3574. http://dx.doi.org/10.1182/blood.v114.22.3574.3574.
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Abstract Abstract 3574 Poster Board III-511 Adoptive transfer of T cell receptor (TCR)-transferred T cells may be an attractive strategy to treat patients with hematological malignancies relapsing after allogeneic stem cell transplantation. Transfer of HLA class I restricted TCRs into CD8+ T cells demonstrated redirected antigen specificity. However, for persistence of anti-leukemic responses in vivo, CD4+ T cells may be important. Therefore, redirecting specificity of CD4+ T cells with well defined HLA class I restricted TCRs might be an attractive strategy for providing help. HLA class I restricted TCRs mostly are CD8-dependent, so for optimal HLA class I restricted reactivity, it was demonstrated that co-expression of the CD8-coreceptor is necessary. The CD8 molecule is expressed on the T cell surface as an αα or an αβ dimer. The α subunit of the CD8 coreceptor binds to the non-polymorphic residues in the α3 domain of the HLA class I molecules thereby enhancing the avidity of the TCR/MHC complex, and the cytoplasmatic tail of the α subunit directly associates with the protein tyrosine kinase Lck (p56lck), promoting signal transduction after T cell activation. The β subunit of the CD8 coreceptor is able to strengthen the avidity of the CD8/MHC/TCR interaction via its extracellular domain, and the intracellular domain enhances the association with the intracellular molecules p56Lck and LAT. Previously, it was reported that for optimal HLA class I restricted specific reactivity with respect to proliferation, cytokine production and cytotoxicity, co-expression of the CD8αβ; coreceptor was needed whereas co-expression of the CD8αα coreceptor marginally increased HLA class I restricted functional activity. Since the regulation of the introduced TCR as well as the CD8 coreceptor in redirected CD4+ T cells will be mediated by retroviral LTRs, we prefer to co-transfer a signaling deficient CD8 coreceptor, thereby minimizing the risk of overstimulation of the redirected T cells. In this study, we investigated whether co-transfer of a signaling deficient CD8 coreceptor would still result in optimal HLA class I restricted functionality of HLA class I restricted TCR engineered CD4+ T cells. For this purpose, we constructed retroviral constructs encoding either wild type CD8α or CD8β subunits, CD8α subunits in which the LCK binding domain was mutated, CD8 subunits composed of the CD8α extracellular domain coupled to the intracellular CD8β signalling domain, and intracellular truncated CD8α or CD8β subunits. pp65-KYQ specific CD4+ T cells were isolated using the IFNγ capture assay and transduced with HLA class I restricted TCRs. Subsequently, TCR transduced virus specific CD4+ T cells were sorted based on marker gene expression, and transduced with the different CD8α and CD8β combinations. In agreement with previous studies we demonstrate that for optimal helper activity of the HLA class I restricted TCR transferred CD4+ T cells coexpression of the CD8αβ coreceptor was required. T cells produced IFNγ, TNFα and IL-2, upregulated CD40L and proliferated upon antigen specific stimulation of the HLA class I restricted TCR. Truncation of the intracellular domains of the CD8α and CD8β subunits did not change the functionality of the HLA class I restricted TCR transferred CD4+ T cells. Whereas in the thymus both the intracellular and extracellular domains of CD8β contribute independently to positive selection and development of CD8+ T cells, our results demonstrate that for optimal HLA class I restricted functionality of TCR modified virus specific CD4+ T cells only the extracellular domains of the CD8a and β subunits are required and sufficient. Disclosures: No relevant conflicts of interest to declare.
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Saito, Kunie, Makoto Hirokawa, Hiroshi Fukaya, Yoshinari Kawabata, AtAtsushi Komatsuda, JuJunsuke Yamashita, and Ken-Ichi Sawada. "Dendritic Cells Co-Developing from Human CD34+ Cells Following Incubation with Thrombopoietin and Tumor Necrosis Factor-α Phagocytose Self-Megakaryocytic Progenitors and Induce Autologous T-Cell Proliferation." Blood 104, no. 11 (November 16, 2004): 4132. http://dx.doi.org/10.1182/blood.v104.11.4132.4132.
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Abstract Background. Thrombopoietin (TPO) and tumor necrosis factor-α (TNF-α) sustain differentiation and proliferation of CD34+ cells toward dendritic cells (DC) in the presence of multi-acting cytokines. Therefore, we hypothesized that stimulation of human CD34+ cells with TPO and TNF-α might co-develop megakaryocytic progenitors and DC, which may relate to the induction of immune tolerance and autoimmunity in megakaryopoiesis. Materials and Methods. Highly purified human CD34+ cells were cultured in liquid phase with TPO, with or without TNF-α, and induced to undergo megakaryocytic differentiation. We enumerated megakaryocytic progenitor cells using the specific markers CD41, CD42b and CD61, and DC using CD4, CD11c, CD80, CD83, CD86 and CD123. The character and roles of co-developing non-megakaryocytic cells in the presence of TNF-α were analyzed using fluorescent activating cell sorter, enzyme immunohistochemistry, confocal microscopy and autologous mixed lymphocyte reaction (AMLR). Results. When CD34+ cells were cultured for 7 days in the presence of TPO at 100 ng/ml, the generated cells predominantly expressed CD41 (95±2%), CD42b (54±12%) and CD61 (96±2%), while rarely expressed CD11c (1.6±1.3%), CD80 (0.1±0.1%), CD83 (0.8±0.6%) or CD86 (3.3±1.9%). In contrast, addition of TNF-α at 100 ng/ml significantly decreased cells expressing CD41 (3.0±0.6%), CD42b (3.3±1.0%) or CD61 (3.2±0.9%), but did not affect the number of total cells. In the presence of TNF-α, the generated cells expressed HLA class I (100%) and HLA class II (100%), and a substantial number of cells became positive for CD11c (37±1%), even costimulatory molecules, such as CD80 (2.4±1.9%), D83 (8±4%) and CD86 (18±7%). TNF-α induced apoptosis of megakaryocytic cells. Immature CD11c+ DC was physically associated with apoptotic and CD61+ cells and was capable of endocytosing CD61+ cells. All of CD11c+ cells co-expressed c-mpl, CD4 and CD123, and about a half of CD11c+ cells co-expressed CD86. Cells generated by TNF-α and TPO (DC: TPO+TNF-α) induced autologous T cell proliferation in AMLR assay, however, cells generated by TNF-α alone (DC: TNF-α) did not (Figure 1A). Immunophenotypic analysis of both populations showed the higher expression of co-stimulatory molecules such as CD80, CD83 and CD86 in cells generated by TNF-α and TPO (Figure 1B). Conclusions. Non-megakaryocytic cells co-generated from human CD34+ cells during megakaryocytic differentiation in the presence of TPO and TNF-α express DC phenotypes. The CD4+/CD11c+/CD123+ DC subset physically and selectively associates with developing immature megakaryocytic cells and then obtains and captures self-substances and are functional in AMLR. These findings suggest that DC generated from human CD34+ cells under megakaryocytic and inflammatory co-stimuli obtain a functional role and possibly leading to the antigen presentation to induce immunity or tolerance against megakaryocytic cells and/or platelets. Figure Figure
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Binsky-Ehrenreich, I., A. Marom, M. C. Sobotta, L. Shvidel, A. Berrebi, I. Hazan-Halevy, S. Kay, et al. "CD84 is a survival receptor for CLL cells." Oncogene 33, no. 8 (February 25, 2013): 1006–16. http://dx.doi.org/10.1038/onc.2013.31.
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Sorg, Rüdiger V., Gesine Kögler, and Peter Wernet. "Identification of Cord Blood Dendritic Cells as an Immature CD11c− Population." Blood 93, no. 7 (April 1, 1999): 2302–7. http://dx.doi.org/10.1182/blood.v93.7.2302.
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Abstract Dendritic cells (DC) are the main stimulators of primary T-cell responses and, thus, probably play a role in the immune reactions after stem cell transplantation. Very little is known about DC in cord blood (CB) and about their potential involvement in the low incidence and severity of acute graft-versus-host disease after CB transplantation. Here, CBDC were identified as a HLA-DR+ cell population, lacking the CD3, CD11b, CD14, CD16, CD19, CD34, CD56, and glycophorin A lineage markers (lin). This lin−/HLA-DR+population represented 0.3% ± 0.1% (mean ± SD; range, 0.1% to 0.6%; n = 15) of CB mononuclear cells, and CB contained 5.4 ± 3.2 × 103 CBDC/mL (1.8 to 13.0 × 103; n = 15). CBDC expressed CD4, CD11a, CD18, CD45RA, CD50, CD54, and CD123, but showed no expression of CD1a, CD11c, CD33, CD40, CD45R0, CD80, CD83, and CD86 and only limited expression of CD58, CD102, and CD116. Despite this immature phenotype, immunomagnetically lin−-enriched CBDC were potent stimulators of allogeneic CB T cells. As few as 266 ± 107 (193 to 530; n = 10) lin−/HLA-DR+ CBDC stimulated a significant response. However, CBDC failed to take up protein or peptide antigens. Thus, in CB there is a prevalence of a DC subpopulation, resembling the CD11c− DC identified in tonsils, the so-called plasmacytoid T cells, which may exert a function distinct from the CD11c+ DC subpopulation.
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Sorg, Rüdiger V., Gesine Kögler, and Peter Wernet. "Identification of Cord Blood Dendritic Cells as an Immature CD11c− Population." Blood 93, no. 7 (April 1, 1999): 2302–7. http://dx.doi.org/10.1182/blood.v93.7.2302.407a25_2302_2307.
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Dendritic cells (DC) are the main stimulators of primary T-cell responses and, thus, probably play a role in the immune reactions after stem cell transplantation. Very little is known about DC in cord blood (CB) and about their potential involvement in the low incidence and severity of acute graft-versus-host disease after CB transplantation. Here, CBDC were identified as a HLA-DR+ cell population, lacking the CD3, CD11b, CD14, CD16, CD19, CD34, CD56, and glycophorin A lineage markers (lin). This lin−/HLA-DR+population represented 0.3% ± 0.1% (mean ± SD; range, 0.1% to 0.6%; n = 15) of CB mononuclear cells, and CB contained 5.4 ± 3.2 × 103 CBDC/mL (1.8 to 13.0 × 103; n = 15). CBDC expressed CD4, CD11a, CD18, CD45RA, CD50, CD54, and CD123, but showed no expression of CD1a, CD11c, CD33, CD40, CD45R0, CD80, CD83, and CD86 and only limited expression of CD58, CD102, and CD116. Despite this immature phenotype, immunomagnetically lin−-enriched CBDC were potent stimulators of allogeneic CB T cells. As few as 266 ± 107 (193 to 530; n = 10) lin−/HLA-DR+ CBDC stimulated a significant response. However, CBDC failed to take up protein or peptide antigens. Thus, in CB there is a prevalence of a DC subpopulation, resembling the CD11c− DC identified in tonsils, the so-called plasmacytoid T cells, which may exert a function distinct from the CD11c+ DC subpopulation.
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Luo, Zhuanbo, Yun Wang, Yanru Lou, Chao Cao, Richard Hubbard, Ning Xu, and Xiaoping Huang. "Unfavorable clinical implications of peripheral blood CD44+ and CD54+ lymphocytes in patients with lung cancer undergoing chemotherapy." International Journal of Biological Markers 33, no. 2 (November 15, 2017): 208–14. http://dx.doi.org/10.5301/ijbm.5000309.
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Background: There is an unmet need for identification of additional prognostic markers for lung cancer. The aim of this study was to identify novel clinical and immunological predictors of prognosis in lung cancer patients. Methods: Lymphocyte subsets CD3+, CD4+, CD8+, CD4+/8+, CD25+, CD69+, CD44+ and CD54+ were quantified in peripheral blood using flow cytometry, for 203 newly diagnosed lung cancer patients and 120 healthy controls. Results: The levels of CD3+, CD4+, CD8+, CD4+/CD8+ and CD69+ lymphocytes were significantly lower in patients with lung cancer compared with the healthy control group, while CD54+ and CD44+ lymphocytes were significantly higher. In stage III/IV patients with lymph node metastasis or distant metastasis, the levels of CD44+ and CD54+ lymphocytes were significantly increased compared with patients with stage I/II disease (p<0.05). The levels of CD44+ and CD54+ lymphocytes markedly reduced after chemotherapy, and follow-up analysis indicated that patients found without increase of CD44+ and CD54+ lymphocytes after chemotherapy had survival advantages. Independent predictors of survival in lung cancer patients included clinical stage (hazard ratio [HR] = 2.791; 95% confidence interval [95% CI], 1.42-3.54, p<0.001), CD44+ lymphocytes (HR = 1.282; 95% CI, 1.02-1.49, p = 0.002) and CD54+ lymphocytes (HR = 1.475; 95% CI, 1.22-1.73, p = 0.003). Elevated levels of CD44+ and CD54+ lymphocytes correlated with poor prognosis in lung cancer patients. Conclusions: Peripheral blood lymphocyte subsets in patients with lung cancer are different from those in healthy people, and circulating CD44+ and CD54+ lymphocytes seem to be a promising criterion to predict survival in lung cancer patients undergoing chemotherapy.
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Kolpakov, Sergey A., Elena P. Kolpakova, Anastasia O. Sitkovskaya, Elena Yu Zlatnik, Svetlana Yu Filippova, Elena S. Bondarenko, Vladimir E. Kolesnikov, et al. "Generation of dendritic cells using viral lysate of tumor cells in vitro." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15202-e15202. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15202.
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e15202 Background: The purpose of the study was to investigate the effect of a new unclassified rotavirus on the effectiveness of maturation of dendritic cells (DC) and their activation of lymphocytes in vitro. Methods: Strain No.100 of the RVK virus was isolated by S.A. Kolpakov and characterized as rotavirus. U87MG cell lysate (glioblastoma) was obtained by incubation with 108 RVK particles in the DMEM medium with L-glutamine for 72 hours; a cytopathic effect was observed. Immature DCs were cultured for 7 days in the presence of IL-4 and GM-CSF. For antigen loading of DCs, we used the following options for 48 h: a) U87MG lysate obtained by repeated freeze-thaw cycles (TL); b) U87MG lysate obtained by co-cultivation with RVK (VTL); c) RVK. To assess the DC ability to activate autologous lymphocytes, they were co-cultured for 5 days in a 3:1 ratio. Results: The use of VTL culture for DC loading caused an increase in the expression of mature DC (mDC) markers compared to TL: the number of CD83+/CD86+ cells increased by more than 2 times, CD83+/CD80+ by 1.2 times, CD83+HLA-DR - by 5.5 times. With VTL, expression of markers of immature DCs (CD1a, CD14) was minimal. The use of RVK as an antigen induced the generation of DCs from monocytes, but their maturation was much less pronounced: a significant increase in the membrane expression of CD86, but not CD83, was determined. These DCs demonstrated a higher expression of markers of immature DCs, compared to stimulation with cell lysates (both TL and VTL): CD1a and CD14; CD80+/CD86+ level was the highest among all options. Analysis of the DC effect on co-cultivated lymphocytes showed that DCs loaded with RVK, both alone and as part of VTL, stimulated predominantly the NKT subpopulation. The same samples contained more T lymphocytes, activated CD4+ and CD8+ compared to samples stimulated by TL. However, the samples co-cultivated with VTL contained the maximal amount of CD4+/CD25+/CD127dim phenotypically corresponding to Tregs. Conclusions: The antigen loading of immature DCs with RVK alone causes their activation, but not maturation, which is not realized in typical terms of the DC generation from blood monocytes. The presence of RVK, including in VTL, has a stimulating effect on NKT lymphocytes suggesting the possible generation of specific highly active cytotoxic lymphocytes.
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Yan, Q., V. N. Malashkevich, A. Fedorov, E. Fedorov, E. Cao, J. W. Lary, J. L. Cole, S. G. Nathenson, and S. C. Almo. "Structure of CD84 provides insight into SLAM family function." Proceedings of the National Academy of Sciences 104, no. 25 (June 11, 2007): 10583–88. http://dx.doi.org/10.1073/pnas.0703893104.
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Reindel, R., J. Bischof, K. Y. A. Kim, J. M. Orenstein, M. B. Soares, S. C. Baker, S. T. Shulman, et al. "CD84 is markedly up-regulated in Kawasaki disease arteriopathy." Clinical & Experimental Immunology 177, no. 1 (June 9, 2014): 203–11. http://dx.doi.org/10.1111/cei.12327.
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Binsky-Ehrenreich, Inbal, Ayelet Marom, Mirko Sobota, Frida Lantner, Nurit Harpaz, Michal Haran, Yair Herishanu, and Idit Shachar. "2.1 CD84 is a Survival Receptor for CLL Cells." Clinical Lymphoma Myeloma and Leukemia 11 (October 2011): S160. http://dx.doi.org/10.1016/j.clml.2011.09.034.
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Gonzalez-Juarrero, Mercedes, and Ian M. Orme. "Characterization of Murine Lung Dendritic Cells Infected with Mycobacterium tuberculosis." Infection and Immunity 69, no. 2 (February 1, 2001): 1127–33. http://dx.doi.org/10.1128/iai.69.2.1127-1133.2001.
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ABSTRACT Lung dendritic cells were identified by immunohistochemistry in lung tissue sections from C57BL/6 mice. Following isolation from the lungs using CD11c magnetic beads, the flow cytometric analysis of I-Ab+ and CD11c+ cells indicated a mixed population of dendritic cells at different stages of maturation, with most expressing an immature phenotype. When cultured for 7 days with recombinant murine granulocyte-macrophage colony-stimulating factor, 99% of cells were CD11c+ and had a morphology typical of immature dendritic cells. These cells were negative for CD34, CD14, and CD8α antigens but expressed low levels of the myeloid marker F4/80 and moderate levels of MAC3. All expressed high levels of CD11a (LFA-1), CD11b (Mac1), and CD54 antigens, with low levels of class II major histocompatibility complex. Most cells expressed CD80 but only a small percentage of cells were positive for CD40 and CD86. Both overnight and 7-day cultures of lung dendritic cells were able to phagocytose Mycobacterium tuberculosis, and this was associated with the production of interleukin-12 and stimulation of both naı̈ve and immune T cells to produce gamma interferon.
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Sawada, Kenichi, Makoto Hirokawa, Kayo Inaba, Hiroshi Fukaya, Yoshinari Kawabata, Atsushi Komatsuda, Junsuke Yamashita, and Kunie Saito. "Phagocytosis of Co-Developing Megakaryocytic Progenitors by Dendritic Cells in the Culture with Thrombopoietin and Tumor Necrosis Factor-α: Possible Role in Hemophagocytic Syndrome." Blood 106, no. 11 (November 16, 2005): 3082. http://dx.doi.org/10.1182/blood.v106.11.3082.3082.
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Abstract Background. Tumor necrosis factor-α (TNF-α) and thrombopoietin (TPO) have been shown to sustain differentiation and proliferation of CD34+ cells toward dendritic cells (DCs) in the presence of multi-acting cytokines. We hypothesized that co-stimulation of TPO and TNF-α generate megakaryocytic progenitors and DCs together from human CD34+ cells and that interaction of these cells may provide a physiological and/or a pathological role of DCs in megakaryopoiesis. Materials and Methods. Highly purified human CD34+ cells were cultured with TPO, with or without TNF-α, in plasma-depleted medium and induced to undergo megakaryocytic differentiation. We enumerated megakaryocytic progenitor cells using the specific markers CD41, CD42b, and CD61, and DCs using CD4, CD11c, CD80, CD83, CD86, and CD123. The character and roles of co-developing non-megakaryocytic cells in the presence of TNF-α were analyzed by fluorescence-activated cell sorter, enzyme immunohistochemistry, confocal microscopy, and autologous mixed lymphocyte reaction. Cytokine production was assessed using a cytometric bead array system. Results. When CD34+ cells were cultured for 7 days in the presence of TPO, the generated cells predominantly expressed CD41 (95±2%), CD42b (54±12%), and CD61 (96±2%), while rarely expressing CD11c (1.6±1.3%), CD80 (0.1±0.1%), CD83 (0.8±0.6%), or CD86 (3.3±1.9%). The addition of TNF-α significantly decreased the number of cells expressing CD41 (3.0±0.6%), CD42b (3.3±1.0%), or CD61 (3.2±0.9%), but did not affect the number of total cells. In the presence of TNF-α, the generated cells expressed major histocompatibility complex (MHC) class I (100%) plus MHC class II (100%). A substantial number of cells became positive for CD11c (37±1%), and even co-stimulatory molecules such as CD80 (2.4±1.9%), CD83 (8±4%), and CD86 (18±7%). Immature CD11c+ DCs were physically associated with apoptotic and CD61+ cells and capable of endocytosing CD61+ cells. Most of the CD11c+ cells co-expressed the c-mpl TPO receptor, CD4, and CD123 and about one half of CD11c+ cells co-expressed CD86. The DCs generated by TNF-α and TPO, but not those by TNF-α alone, facilitated autologous T cell proliferation in some extent, although cytokine production from activated T cells were low. We also confirmed engulfment of CD61+ cells and their fragment by CD11c+ cells in bone marrow cells from patients with hemophagocytic syndromes. Conclusions. This is the first report showing that in the presence of TNF-α, the non-megakaryocytic cells with typical feature of DCs are co-generated from human CD34+ cells during megakaryocytic differentiation by TPO. The CD4+ CD11c+ CD123+ DCs physically associates with and phagocytose developing or dying immature megakaryocytic cells. Similar phenomenon showing engulfment of CD61+ fragment by CD11c+ cells was also observed in bone marrow cells from patients with hemophagocytic syndrome. Therefore, it may be conceivable that DCs with phagocytic activity during the development in bone marrow may play a crucial role in the maintenance of tolerance for self-substances derived from hematopoietic progenitor cells.
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KRAUSE, Stefan W., Michael REHLI, Sven HEINZ, Reinhard EBNER, and Reinhard ANDREESEN. "Characterization of MAX.3 antigen, a glycoprotein expressed on mature macrophages, dendritic cells and blood platelets: identity with CD84." Biochemical Journal 346, no. 3 (March 7, 2000): 729–36. http://dx.doi.org/10.1042/bj3460729.
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MAX.3 is a monoclonal antibody that preferentially reacts with mature macrophages (MAC), monocyte-derived dendritic cells, megakaryocytes and platelets. In this study, we describe the characterization, purification and identification of the MAX.3 antigen. Immunoprecipitation and SDS/PAGE revealed different molecular masses of MAX.3 antigen in MAC (60-90 kDa) and platelets (58-64 kDa), whereas a similar size (45 kDa) was observed in both cell types after digestion with N-glycosidase F. Lectin affinity and sequential treatment with different glycosidases suggests complex type glycosylation of MAX.3 antigen in MAC and hybrid type glycosylation in platelets. Amino acid sequencing led to the identification of a corresponding cDNA clone and showed its identity to the sequence of the CD84 antigen, a member of the CD2 family of cell surface molecules. MAX.3/CD84 was further studied by immunohistochemistry and a variable expression was found on tissue MAC, confirming this antigen to be mainly a marker for MAC in situ.
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Scott, David R., Taylor A. Doherty, Naseem Khorram, Sean Lund, Rachel Baum, Jinny Chang, Peter Rosenthal, Andrew Beppu, Marina Miller, and David H. Broide. "Allergen Challenge Increases Peripheral Blood CD84+ ILC2 In Allergic Rhinitis." Journal of Allergy and Clinical Immunology 133, no. 2 (February 2014): AB237. http://dx.doi.org/10.1016/j.jaci.2013.12.843.
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Hirano, Naoto, Marcus O. Butler, and Lee M. Nadler. "4-1BB (CD137) or CD40 Signaling Fails To Improve the Expansion of Antigen Specific T Cells Demonstrated with Engagement of TCR, CD28 and CD83 Ligand." Blood 104, no. 11 (November 16, 2004): 2665. http://dx.doi.org/10.1182/blood.v104.11.2665.2665.
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Abstract Following the engagement of the T cell receptor by HLA class I and antigenic peptide, naïve CD8+ T cells are primed to receive one or more costimulatory signals. Some of these signals, which are upregulated on and delivered by mature dendritic cells, include members of the immunoglobulin superfamily such as CD80 and CD83. Using a K562 derived artificial antigen presenting cell (aAPC) that expresses HLA-A2, CD80, and CD83, we have shown that the coengagement of CD83 ligand:CD83 and CD28:CD80 induces prolonged and preferential expansion of antigen specific CD8+ T cells. Furthermore, we have found that CD28:CD80 signaling is required for the induction of CD83 ligand expression on peripheral T cells. In order to identify additional immunoaccessory molecules that can augment this response, we have developed a system to efficiently transfer any chosen molecule into aAPC. This provides an excellent platform for studying a potentially immunogenic molecule given the relative lack of immunoaccessory molecules expressed by K562 (i.e. no expression of CD40, CD40 ligand, CD83, CD86, 4-1BB, 4-1BB ligand, OX40, OX40 ligand, HLA class I, or HLA class II). Following the transduction of a candidate molecule under study, the stimulatory capacity of a supertransduced aAPC can be compared to parental aAPC. Attractive candidates include members of the TNF superfamily since they have been shown to deliver important costimulatory signals to T cells. It has been suggested that 4-1BB signaling supports the survival of newly generated effector CD8+ T cells and that CD40 signaling confers “CD4+ T cell-like” help directly to CD8+ T cells. However, the impact of each of these molecules on the stimulation and expansion of antigen specific T cells has not been exhaustively studied. In this report, we transfected aAPC with either 4-1BB ligand or CD40 ligand, allowing us to compare the stimulatory capacity of aAPC/CD40 ligand, aAPC/4-1BB ligand and parental aAPC. We stimulated HLA-A2 positive CD8+ T cells from healthy donors three times at weekly intervals with A2-restricted MART1 peptide pulsed onto either irradiated aAPC/CD40 ligand, aAPC/4-1BB ligand or parental aAPC. Between the stimulations, cells were treated with IL2 and IL15 every three days. When MART1 peptide pulsed aAPC/CD40 ligand were used as stimulators, the total number of CD8+ T cells and number of MART1 specific CD8+ T cells was slightly smaller. IFN-γ ELISPOT analysis revealed that functional avidity of T cell receptors on MART1 specific CD8+ T cells was similar whether they were stimulated by aAPC/CD40 ligand or parental aAPC. These results indicate that CD40 ligand, at least in the human setting, does not directly provide “CD4+ T cell-like” help to antigen-specific CD8+ T cells. In contrast, stimulation with peptide pulsed aAPC/4-1BB ligand did generate a larger total number of CD8+ T cells. Surprisingly, however, most of these T cells were not antigen specific. In fact, significantly fewer MART1 specific CD8+ T cells were generated by aAPC/4-1BB ligand compared to aAPC alone. These results suggest that, unlike CD80 and CD83, 4-1BB ligand delivers a costimulatory signal resulting in the non-specific expansion of CD8+ T cells. This work demonstrates the versatility of our system to dissect the function of particular immunoaccessory molecules and determine the optimal conditions in the stimulation and expansion of antigen-specific human CD8+ T cells ex vivo.
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Ryncarz, Rita E., and Claudio Anasetti. "Expression of CD86 on Human Marrow CD34+ Cells Identifies Immunocompetent Committed Precursors of Macrophages and Dendritic Cells." Blood 91, no. 10 (May 15, 1998): 3892–900. http://dx.doi.org/10.1182/blood.v91.10.3892.
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Abstract Macrophages and dendritic cells derive from a hematopoietic stem cell and the existence of a common committed progenitor has been hypothesized. We have recently found in normal human marrow a subset of CD34+ cells that constitutively expresses HLA-DR and low levels of CD86, a natural ligand for the T cell costimulation receptor CD28. This CD34+ subset can elicit responses from allogeneic T cells. In this study, we show that CD34+/CD86+ cells can also present tetanus toxoid antigen to memory CD4+ T cells. CD86 is expressed at low levels in macrophages and high levels in dendritic cells. Therefore, we have tested the hypothesis that CD34+/CD86+ cells are the common precursors of both macrophages and dendritic cells. CD34+/CD86+ marrow cells cultured in granulocyte-macrophage colony-stimulating factor (GM-CSF)–generated macrophages. In contrast, CD34+/CD86− cells cultured in GM-CSF generated a predominant population of granulocytes. CD34+/CD86+ cells cultured in GM-CSF plus tumor necrosis factor-α (TNF-α) generated almost exclusively CD1a+/CD83+ dendritic cells. In contrast, CD34+/CD86− cells cultured in GM-CSF plus TNF-α generated a variety of cell types, including a small population of dendritic cells. In addition, CD34+/CD86+ cells cultured in granulocyte colony-stimulating factor failed to generate CD15+granulocytes. Therefore, CD34+/CD86+ cells are committed precursors of both macrophages and dendritic cells. The ontogeny of dendritic cells was recapitulated by stimulation of CD34+/CD86− cells with TNF-α that induced expression of CD86. Subsequent costimulation of CD86+cells with GM-CSF plus TNF-α lead to expression of CD83 and produced terminal dendritic cell differentiation. Thus, expression of CD86 on hematopoietic progenitor cells is regulated by TNF-α and denotes differentiation towards the macrophage or dendritic cell lineages.
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Ryncarz, Rita E., and Claudio Anasetti. "Expression of CD86 on Human Marrow CD34+ Cells Identifies Immunocompetent Committed Precursors of Macrophages and Dendritic Cells." Blood 91, no. 10 (May 15, 1998): 3892–900. http://dx.doi.org/10.1182/blood.v91.10.3892.3892_3892_3900.
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Macrophages and dendritic cells derive from a hematopoietic stem cell and the existence of a common committed progenitor has been hypothesized. We have recently found in normal human marrow a subset of CD34+ cells that constitutively expresses HLA-DR and low levels of CD86, a natural ligand for the T cell costimulation receptor CD28. This CD34+ subset can elicit responses from allogeneic T cells. In this study, we show that CD34+/CD86+ cells can also present tetanus toxoid antigen to memory CD4+ T cells. CD86 is expressed at low levels in macrophages and high levels in dendritic cells. Therefore, we have tested the hypothesis that CD34+/CD86+ cells are the common precursors of both macrophages and dendritic cells. CD34+/CD86+ marrow cells cultured in granulocyte-macrophage colony-stimulating factor (GM-CSF)–generated macrophages. In contrast, CD34+/CD86− cells cultured in GM-CSF generated a predominant population of granulocytes. CD34+/CD86+ cells cultured in GM-CSF plus tumor necrosis factor-α (TNF-α) generated almost exclusively CD1a+/CD83+ dendritic cells. In contrast, CD34+/CD86− cells cultured in GM-CSF plus TNF-α generated a variety of cell types, including a small population of dendritic cells. In addition, CD34+/CD86+ cells cultured in granulocyte colony-stimulating factor failed to generate CD15+granulocytes. Therefore, CD34+/CD86+ cells are committed precursors of both macrophages and dendritic cells. The ontogeny of dendritic cells was recapitulated by stimulation of CD34+/CD86− cells with TNF-α that induced expression of CD86. Subsequent costimulation of CD86+cells with GM-CSF plus TNF-α lead to expression of CD83 and produced terminal dendritic cell differentiation. Thus, expression of CD86 on hematopoietic progenitor cells is regulated by TNF-α and denotes differentiation towards the macrophage or dendritic cell lineages.
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Breda, Philippe Christophe, Thorsten Wiech, Catherine Meyer-Schwesinger, Florian Grahammer, Tobias Huber, Ulf Panzer, Gisa Tiegs, and Katrin Neumann. "Renal proximal tubular epithelial cells exert immunomodulatory function by driving inflammatory CD4+ T cell responses." American Journal of Physiology-Renal Physiology 317, no. 1 (July 1, 2019): F77—F89. http://dx.doi.org/10.1152/ajprenal.00427.2018.
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In immune-mediated glomerular diseases like crescentic glomerulonephritis (cGN), inflammatory CD4+ T cells accumulate within the tubulointerstitial compartment in close contact to proximal and distal tubular epithelial cells and drive renal inflammation and tissue damage. However, whether renal epithelial cell populations play a role in the pathogenesis of cGN by modulating CD4+ T cell responses is less clear. In the present study, we aimed to investigate the potential of renal epithelial cells to function as antigen-presenting cells, thereby stimulating CD4+ T cell responses. Using a FACS-based protocol that allowed comparative analysis of cortical epithelial cell populations, we showed that particularly proximal tubular epithelial cells (PTECs) express molecules linked with antigen-presenting cell function, including major histocompatibility complex class II (MHCII), CD74, CD80, and CD86 in homeostasis and nephrotoxic nephritis, a murine model of cGN. Protein expression was visualized at the PTEC single cell level by imaging flow cytometry. Interestingly, we found inflammation-dependent regulation of epithelium-expressed CD74, CD80, and CD86, whereas MHCII expression was not altered. Antigen-specific stimulation of CD4+ T cells by PTECs in vitro supported CD4+ T cell survival and induced CD4+ T cell activation, proliferation, and inflammatory cytokine production. In patients with antineutrophil cytoplasmic antibody-associated glomerulonephritis, MHCII and CD74 were expressed by both proximal and distal tubules, whereas CD86 was predominantly expressed by proximal tubules. Thus, particularly PTECs have the potential to induce an inflammatory phenotype in CD4+ T cells in vitro, which might also play a role in the pathology of immune-mediated kidney disease.
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Gunes, Emine Gulsen, Hadas Lewinsky, Domenico Viola, Enrico Caserta, Michael Rosenzweig, Myo Htut, James Sanchez, et al. "CD84: A Potential Novel Therapeutic Target in the Multiple Myeloma Microenvironment." Clinical Lymphoma Myeloma and Leukemia 19, no. 10 (October 2019): e148-e149. http://dx.doi.org/10.1016/j.clml.2019.09.247.
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Jones, Monica, Bruce Blazar, Zachary Zimmerman, and Robert B. Levy. "Transplanted Donor APC Co-Stimulatory Molecule Expression Is Required To Elicit Host T Cell Resistance in MHC-Matched Allogeneic BMT Recipients Following Reduced Intensity Conditioning." Blood 108, no. 11 (November 16, 2006): 620. http://dx.doi.org/10.1182/blood.v108.11.620.620.
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Abstract Controlling host resistance to hematopoietic progenitor cell grafts is crucial for successful engraftment and the induction and maintenance of immune tolerance. We are studying the induction and regulation of the pathways that lead to T cell resistance in a well characterized minor histocompatibility antigen (MiHA) matched allogeneic transplant model under reduced intensity conditioning (RIC). B6 recipients transplanted with MHC matched allogeneic TCD-BM following RIC resist donor grafts as evidenced by expansion of anti-MiHA specific CD8 T cells and transient peripheral blood donor chimerism. To initially examine the involvement of CD80/CD86 expression in this resistance, mabs to CD80 and CD86 were administered at the time of transplant of BALB.B (H2b, 4x106 TCD-BMC) BMC into 5.5 Gy TBI conditioned B6-wt (H2b) mice. Donor (Ly9.1+) cells were not rejected in such recipients. We next investigated the requirement of CD80/86 expression on recipient cells with respect to development of resistance. C3H.SW (H2b) TCD-BMC were transplanted into B6-wt or B6-CD80−/−86−/− (H2b) mice as above. Donor chimerism in both B6-wt and B6-CD80−/−86−/− recipients was transient indicating resistance had been elicited against the donor BM. BM deficient in both CD80 and CD86 was then transplanted into MHC matched recipients following RIC. In contrast to B6-wt BMC grafts, transplantation of B6-CD80−/−86−/− BM failed to result in rejection leading to a sustained and high level of donor cell chimerism. These results suggested direct recognition of MiHA on donor APC was sufficient to elicit resistance. Since wt BMC transplants into CD4−/− recipients demonstrated CD4+ T cell function is critical for resistance in this model, we hypothesized that activated host CD4 T cell recognition of donor APC resulted in the upregulation of CD80/CD86 co-stimulatory molecules. B6-wt and B6-CD40L deficient mice were transplanted with BALB.B (H2b) TCD-BM. As predicted, B6-wt recipients again rejected the donor BM within 2–3 wks of transplant. The resistance was evidenced by the generation of a host CD8+ T cell response against the immunodominant donor MiHA H60 (elevated % of tetramer staining host H60+CD8+ T cells). In contrast, B6-CD40L deficient recipients demonstrated stable chimerism for >50 days post-transplant and did not generate H60+CD8+ T cells. To specifically examine the requirement of CD40L on CD4 T cells in the host, B6-CD4−/− mice (5.5Gy) were transplanted with BALB.B TCD-BM together with CD4+ T cells from B6-wt or B6-CD40L−/− mice. Recipients co-transplanted with B6-wt CD4+ T cells rejected their grafts 2–3 wks post-transplant whereas recipients of CD4+ T cells from B6-CD40L−/− donors expressed donor cell chimerism and failed to resist the MHC-matched marrow allograft. In total, we interpret the results to demonstrate a requirement for host CD4 T cells to recognize donor MiHA and undergo alloantigen induced activation resulting in CD40L induction of CD80/86 on donor APC. These interactions then result in host CD8 T cell effector activity which inhibits donor engraftment. Since recipients containing anti-donor specific CD8 memory cells were found to resist MHC-matched HCT containing CD80/86 deficient APC, the present findings support the notion that direct recognition of donor APC is crucial to elicit T cell mediated resistance to hematopoietic engraftment in ‘naive’ RIC MHC-matched allogeneic recipients.
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Brosbøl-Ravnborg, Anne, Bettina Bundgaard, and Per Höllsberg. "Synergy between Vitamin D3and Toll-Like Receptor Agonists Regulates Human Dendritic Cell Response during Maturation." Clinical and Developmental Immunology 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/807971.
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Human dendritic cells (DC) can be differentiated from blood monocytes in the presence of GM-CSF and IL-4 and matured by lipopolysaccharide (LPS). Vitamin D3inhibits the maturation of human DC measured by changes in surface expression of HLA-DR, CD14, CD40, CD80, CD83, and CD86. We here examine the function of vitamin D3during DC maturation. One of the earliest changes to LPS-induced maturation was an increase in CD83 expression. Vitamin D3inhibited the increase in expression of HLA-DR, CD40, CD80, CD83, and CD86 and the decrease in expression of CD14, which was paralleled morphologically by vitamin D3-induced inhibition of dendritic cell differentiation. Vitamin D3acted in synergy with the TLR agonists LPS and peptidoglycan (PGN) in inducing IL-6, IL-8, and IL-10, whereas vitamin D3completely inhibited LPS-induced secretion of IL-12. The synergy occurred at concentrations where neither vitamin D3nor the TLR agonists alone induced measurable cytokine secretion. Both LPS and PGN enhanced the level of the vitamin D3receptor (VDR). Taken together, these data demonstrated that vitamin D3and TLR agonists acted in synergy to alter secretion of cytokines from human DC in a direction that may provide an anti-inflammatory environment.
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Szabolcs, P., D. Avigan, S. Gezelter, DH Ciocon, MA Moore, RM Steinman, and JW Young. "Dendritic cells and macrophages can mature independently from a human bone marrow-derived, post-colony-forming unit intermediate." Blood 87, no. 11 (June 1, 1996): 4520–30. http://dx.doi.org/10.1182/blood.v87.11.4520.bloodjournal87114520.
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CD34+ precursors in normal human bone marrow (BM) generate large numbers of dendritic cells alongside macrophages and granulocytic precursors when cultured for 12 to 14 days in c-kit ligand, granulocyte- macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNF-alpha). This study reports an intermediate cell type that develops by day 6, and has the potential to differentiate into either macrophages or dendritic cells. When the d6 progeny are depleted of mature macrophages and residual CD34+ precursors, a discrete CD14+ HLA-DR+ population persists in addition to immunostimulatory CD14- HLA- DR() dendritic cells. Half of the CD14+ HLA-DR+ population is in cell cycle (Ki-67+), but colony-forming units (CFUs) are no longer detectable. The calls are c-fms+, but lack myeloperoxidase and nonspecific esterase. They also possess substantial phagocytic and allostimulatory activity. These post-CFU, CD14+ HLA-DR+ intermediates develop into typical macrophages when recultured in the absence of exogenous cytokines. M-CSF supports up to approximately 2.5-fold expansion of macrophage progeny. In contrast, the combination of GM-CSF and TNF-alpha supports quantitative differentiation into dendritic cells, lacking c-fms, CD14, and other macrophage properties, and expressing HLA-DR, CD1a, CD83, CD80, CD86, and potent allostimulatory activity. Therefore, normal CD34+ BM precursors can generate a post-CFU bipotential intermediate in the presence of c-kit ligand, GM-CSF, and TNF-alpha. This intermediate cell type will develop along the dendritic cell pathway when macrophages are removed and GM-CSF and TNF-alpha are provided. Alternatively, it can differentiate along a macrophage pathway when recultured with or without M-CSF.
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Zahran, Asmaa M., Khaled Saad, Khalid I. Elsayh, Abobakr Abdelmoghny, Mohamed Diab Aboul-Khair, Ali Sobhy, Yasser F. Abdel-Raheem, et al. "Myeloid-Derived Suppressor Cells and Costimulatory Molecules in Children With Allergic Rhinitis." Annals of Otology, Rhinology & Laryngology 128, no. 2 (November 18, 2018): 128–34. http://dx.doi.org/10.1177/0003489418812902.
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Objectives: The aim of this study is to assess the level of myeloid-derived suppressor cells (MDSCs) and the expression of costimulatory molecules CD80 and CD86 on monocytes and their ligands (CD28) on T-lymphocytes in children with allergic rhinitis (AR). Methods: The study included 60 children with AR and 50 controls. Flow cytometry was performed to analyze MDSCs and the expression of costimulatory molecules CD80 and CD86 on monocytes and their ligands (CD28) on T-lymphocytes. Results: The percentages of total and monocytic MDSCs and the expression of costimulatory molecule CD86 on monocytes were significantly higher in children with AR than in healthy controls. In addition, the expressions of CD28 on CD4+ and CD8+ were significantly elevated in AR patients. Conclusion: The present study demonstrated that the percentages of MDSCs were significantly elevated in AR children. Moreover, the expressions of CD28 on CD4+ and CD8+ were significantly higher in children with AR.
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Butler, Marcus O., Sascha Ansén, Makito Tanaka, Osamu Imataki, Alla Berezovskaya, Mary M. Mooney, Genita Metzler, Matthew I. Milstein, Lee M. Nadler, and Naoto Hirano. "A Series of Human Cell-Based Artificial APC Expands Long-Lived, Th1-Biased, Viral Antigen-Specific CD4+ T Cells with a Central/Effector Memory Phenotpype Restricted by Common HLA-DR Alleles." Blood 116, no. 21 (November 19, 2010): 354. http://dx.doi.org/10.1182/blood.v116.21.354.354.
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Abstract Abstract 354 Adoptive cell therapy utilizes unique mechanisms of action to prevent the development of infections in immunocompromised patients and treat chemotherapy resistant malignancies. In adoptive cell therapy, the major effector cells appear to be CD8+ T cells, since they are armed with antigen-specific effector functions, i.e. cytotoxicity and cytokine secretion. However, the roles of antigen-specific CD4+ T cells in T cell immunity are also critical. In immunocompromised patients adoptively transferred with CMV-specific CD8+ T cells, long-term in vivo persistence was achieved only when CMV-specific CD4+ T cells were also present in vivo. Recently, adoptive transfer of a NY-ESO-1 specific CD4+ T cell clone was reported to induce a complete response in a patient with metastatic melanoma. These results suggest that adoptive cell therapy for infectious diseases and cancer can be improved by infusing both antigen-specific CD4+ helper T cells as well as CD8+ CTL. Unfortunately, however, few versatile systems are available for producing large numbers of antigen-specific human CD4+ T cells for the purpose of adoptive therapy. K562 is a human erythroleukemic cell line, which lacks the expression of HLA class I and II, invariant chain (Ii), and HLA-DM, but does express adhesion molecules such as ICAM-1 and LFA-3. Given this unique immunologic phenotype, K562 has served as a useful tool in clinical cancer immunotherapy trials. Previously, we reported the generation of a K562-based artificial APC (aAPC), which expresses HLA-A2, CD80, and CD83. aAPC/A2 can uniquely support the priming and prolonged expansion of large numbers of antigen-specific CD8+ CTL which display a central/effector memory phenotype, possess potent effector function, and can be maintained in vitro without any feeder cells or cloning. aAPC/A2 is equipped with constitutive proteasome and inducible immunoproteasome machinery and can naturally process and present CD8+ T cell peptides via transduced A2 molecules. We have successfully generated clinical grade aAPC/A2 under cGMP conditions and conducted a clinical trial where patient with advanced melanoma are infused with large numbers of MART1-specific CTL generated ex vivo using aAPC/A2, IL-2 and IL-15. Based on our experience with aAPC/A2 and CD8+ T cells, we have generated a series of novel aAPC (aAPC/DR1, DR3, DR4, DR7, DR10, DR11, DR13, and DR15) to stimulate HLA-DR-restricted antigen-specific CD4+ T cells. K562 has been engineered to express HLA-DRα and β chains as a single HLA allele in conjunction with Ii, HLA-DMα and β chains, CD80 and CD83. CD83 delivers a CD80-dependent T cell stimulatory signal that allows T cells to be long-lived. Following the transduction of Ii, CLIP (class II invariant chain-associated peptide) appeared on the cell surface of aAPC. Furthermore, CLIP expression on aAPC was almost completely abrogated by the introduction of HLA-DM. This result is in accordance with previous studies showing that HLA-DM catalyzes the removal of CLIP from DR thus enabling exogenous peptides to bind to empty DR molecules in late endosomes. In addition to its endogenous pinocytic activity, aAPC was made capable of Fcγ receptor-mediated endocytosis by transduction of CD64. Comparison of naïve aAPC and CD64-transduced aAPC confirmed that Fcγ receptor-mediated endocytosis is more efficient than pinocytosis to take up soluble protein and process and present DR-restricted peptides to CD4+ T cells. Using these standardized and renewable aAPC, we determined novel viral protein-derived DR-restricted CD4+ T cell epitopes and expanded large numbers of viral antigen-specific CD4+ T cells without growing bystander Foxp3+ regulatory T cells. Without any feeder cells or cloning, expansion of CD4+ T cells using aAPC and low dose IL-2 and IL-15 was sustainable up to 150 days. Immunophenotypic analysis using HLA-DR tetramers and specific mAbs revealed that expanded CD4+ T cells were CD45RA−, CD45RO+, CD62L+-, demonstrating a central/effector memory phenotype. Furthermore, intracellular cytokine analysis showed that expanded DR-restricted viral-specific CD4+ T cells secreted IL-2 and IFN-γ but much less IL-4, displaying a Th1-biased phenotype. Taken all together, these results suggest that K562-based aAPC may serve as a translatable platform to generate both antigen-specific CD4+ helper T cells and CD8+ CTL. Disclosures: No relevant conflicts of interest to declare.
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Álvarez-Errico, Damiana, Irene Oliver-Vila, Erola Ainsua-Enrich, Alasdair M. Gilfillan, César Picado, Joan Sayós, and Margarita Martín. "CD84 Negatively Regulates IgE High-Affinity Receptor Signaling in Human Mast Cells." Journal of Immunology 187, no. 11 (November 7, 2011): 5577–86. http://dx.doi.org/10.4049/jimmunol.1101626.
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Wong, Eric B., Chetna Soni, Alice Y. Chan, Phillip P. Domeier, Shwetank, Thomas Abraham, Nisha Limaye, et al. "B Cell–Intrinsic CD84 and Ly108 Maintain Germinal Center B Cell Tolerance." Journal of Immunology 194, no. 9 (March 23, 2015): 4130–43. http://dx.doi.org/10.4049/jimmunol.1403023.
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Gassmann, Hendrik, Kira Schneider, Valentina Evdokimova, Peter Ruzanov, Sebastian J. Schober, Busheng Xue, Kristina von Heyking, et al. "Ewing Sarcoma-Derived Extracellular Vesicles Impair Dendritic Cell Maturation and Function." Cells 10, no. 8 (August 13, 2021): 2081. http://dx.doi.org/10.3390/cells10082081.
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Ewing sarcoma (EwS) is an aggressive pediatric cancer of bone and soft tissues characterized by scant T cell infiltration and predominance of immunosuppressive myeloid cells. Given the important roles of extracellular vesicles (EVs) in cancer-host crosstalk, we hypothesized that EVs secreted by EwS tumors target myeloid cells and promote immunosuppressive phenotypes. Here, EVs were purified from EwS and fibroblast cell lines and exhibited characteristics of small EVs, including size (100–170 nm) and exosome markers CD63, CD81, and TSG101. Treatment of healthy donor-derived CD33+ and CD14+ myeloid cells with EwS EVs but not with fibroblast EVs induced pro-inflammatory cytokine release, including IL-6, IL-8, and TNF. Furthermore, EwS EVs impaired differentiation of these cells towards monocytic-derived dendritic cells (moDCs), as evidenced by reduced expression of co-stimulatory molecules CD80, CD86 and HLA-DR. Whole transcriptome analysis revealed activation of gene expression programs associated with immunosuppressive phenotypes and pro-inflammatory responses. Functionally, moDCs differentiated in the presence of EwS EVs inhibited CD4+ and CD8+ T cell proliferation as well as IFNγ release, while inducing secretion of IL-10 and IL-6. Therefore, EwS EVs may promote a local and systemic pro-inflammatory environment and weaken adaptive immunity by impairing the differentiation and function of antigen-presenting cells.
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Menetrier-Caux, C., G. Montmain, M. C. Dieu, C. Bain, M. C. Favrot, C. Caux, and J. Y. Blay. "Inhibition of the Differentiation of Dendritic Cells From CD34+ Progenitors by Tumor Cells: Role of Interleukin-6 and Macrophage Colony-Stimulating Factor." Blood 92, no. 12 (December 15, 1998): 4778–91. http://dx.doi.org/10.1182/blood.v92.12.4778.
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Abstract The escape of malignant cells from the immune response against the tumor may result from a defective differentiation or function of professional antigen-presenting cells (APC), ie, dendritic cells (DC). To test this hypothesis, the effect of human renal cell carcinoma cell lines (RCC) on the development of DC from CD34+progenitors was investigated in vitro. RCC cell lines were found to release soluble factors that inhibit the differentiation of CD34+ cells into DC and trigger their commitment towards monocytic cells (CD14+CD64+CD1a−CD86−CD80−HLA-DRlow) with a potent phagocytic capacity but lacking APC function. RCC CM were found to act on the two distinct subpopulations emerging in the culture at day 6 ([CD14+CD1a−] and [CD14−CD1a+]) by inhibiting the differentiation into DC of [CD14+CD1a−] precursors and blocking the acquisition of APC function of the [CD14−CD1a+] derived DC. Interleukin-6 (IL-6) and macrophage colony-stimulating factor (M-CSF) were found to be responsible for this phenomenon: antibodies against IL-6 and M-CSF abrogated the inhibitory effects of RCC CM; and recombinant IL-6 and/or M-CSF inhibited the differentiation of DC similarly to RCC CM. The inhibition of DC differentiation by RCC CM was preceeded by an induction of M-CSF receptor (M-CSFR; CD115) and a loss of granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR; CD116) expression at the surface of CD34+cells, two phenomenon reversed by anti–IL-6/IL-6R and anti–M-CSF antibodies, respectively. Finally, a panel of tumor cell lines producing IL-6 and M-CSF induced similar effects. Taken together, the results suggest that the inhibition of DC development could represent a frequent mechanism by which tumor cells will escape immune recognition.
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Menetrier-Caux, C., G. Montmain, M. C. Dieu, C. Bain, M. C. Favrot, C. Caux, and J. Y. Blay. "Inhibition of the Differentiation of Dendritic Cells From CD34+ Progenitors by Tumor Cells: Role of Interleukin-6 and Macrophage Colony-Stimulating Factor." Blood 92, no. 12 (December 15, 1998): 4778–91. http://dx.doi.org/10.1182/blood.v92.12.4778.424k14_4778_4791.
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The escape of malignant cells from the immune response against the tumor may result from a defective differentiation or function of professional antigen-presenting cells (APC), ie, dendritic cells (DC). To test this hypothesis, the effect of human renal cell carcinoma cell lines (RCC) on the development of DC from CD34+progenitors was investigated in vitro. RCC cell lines were found to release soluble factors that inhibit the differentiation of CD34+ cells into DC and trigger their commitment towards monocytic cells (CD14+CD64+CD1a−CD86−CD80−HLA-DRlow) with a potent phagocytic capacity but lacking APC function. RCC CM were found to act on the two distinct subpopulations emerging in the culture at day 6 ([CD14+CD1a−] and [CD14−CD1a+]) by inhibiting the differentiation into DC of [CD14+CD1a−] precursors and blocking the acquisition of APC function of the [CD14−CD1a+] derived DC. Interleukin-6 (IL-6) and macrophage colony-stimulating factor (M-CSF) were found to be responsible for this phenomenon: antibodies against IL-6 and M-CSF abrogated the inhibitory effects of RCC CM; and recombinant IL-6 and/or M-CSF inhibited the differentiation of DC similarly to RCC CM. The inhibition of DC differentiation by RCC CM was preceeded by an induction of M-CSF receptor (M-CSFR; CD115) and a loss of granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR; CD116) expression at the surface of CD34+cells, two phenomenon reversed by anti–IL-6/IL-6R and anti–M-CSF antibodies, respectively. Finally, a panel of tumor cell lines producing IL-6 and M-CSF induced similar effects. Taken together, the results suggest that the inhibition of DC development could represent a frequent mechanism by which tumor cells will escape immune recognition.
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Caux, C., B. Vanbervliet, C. Massacrier, C. Dezutter-Dambuyant, B. de Saint-Vis, C. Jacquet, K. Yoneda, S. Imamura, D. Schmitt, and J. Banchereau. "CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to GM-CSF+TNF alpha." Journal of Experimental Medicine 184, no. 2 (August 1, 1996): 695–706. http://dx.doi.org/10.1084/jem.184.2.695.
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Human dendritic cells (DC) can now be generated in vitro in large numbers by culturing CD34+ hematopoietic progenitors in presence of GM-CSF+TNF alpha for 12 d. The present study demonstrates that cord blood CD34+ HPC indeed differentiate along two independent DC pathways. At early time points (day 5-7) during the culture, two subsets of DC precursors identified by the exclusive expression of CD1a and CD14 emerge independently. Both precursor subsets mature at day 12-14 into DC with typical morphology and phenotype (CD80, CD83, CD86, CD58, high HLA class II). CD1a+ precursors give rise to cells characterized by the expression of Birbeck granules, the Lag antigen and E-cadherin, three markers specifically expressed on Langerhans cells in the epidermis. In contrast, the CD14+ progenitors mature into CD1a+ DC lacking Birbeck granules, E-cadherin, and Lag antigen but expressing CD2, CD9, CD68, and the coagulation factor XIIIa described in dermal dendritic cells. The two mature DC were equally potent in stimulating allogeneic CD45RA+ naive T cells. Interestingly, the CD14+ precursors, but not the CD1a+ precursors, represent bipotent cells that can be induced to differentiate, in response to M-CSF, into macrophage-like cells, lacking accessory function for T cells. Altogether, these results demonstrate that different pathways of DC development exist: the Langerhans cells and the CD14(+)-derived DC related to dermal DC or circulating blood DC. The physiological relevance of these two pathways of DC development is discussed with regard to their potential in vivo counterparts.
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Tjønnfjord, G. E., O. P. Veiby, R. Steen, and T. Egeland. "T lymphocyte differentiation in vitro from adult human prethymic CD34+ bone marrow cells." Journal of Experimental Medicine 177, no. 6 (June 1, 1993): 1531–39. http://dx.doi.org/10.1084/jem.177.6.1531.
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Pluripotent lymphohematopoietic stem cells are probably confined to bone marrow cells expressing CD34 surface molecules. To investigate the capacity of adult human CD34+ bone marrow cells to differentiate along the T lymphoid lineage, we plated purified CD34+ cells from healthy adults in liquid culture on adherent thymic stromal cells prepared from HLA- or blood group-mismatched postnatal thymic tissue. We show that purified CD34+CD3-CD4-CD8- bone marrow cells contained progenitors with the ability to differentiate into CD4+ and CD8+ T lymphocytes expressing surface (s)CD3 and T cell receptor alpha/beta in vitro. These progenitors were found in the CD34+CD2+sCD3-CD4-CD8-, CD34+CD7+sCD3-CD4-CD8-, and CD34+CD2+CD7+sCD3-CD4-CD8-, as well as in the CD34+CD2-sCD3-CD4-CD8-, CD34+CD7-sCD3-CD4-CD8-, and CD34+CD2-CD7-sCD3-CD4-CD8- subsets, indicating that T lymphocyte progenitors sensitive to signals mediated by thymic stroma in vitro are not restricted to CD34+ cells already coexpressing early T lymphocyte-associated markers. Finally, we show that T lymphopoiesis was enhanced by c-kit ligand.
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Pelikan, Zdenek. "Expression of Surface Markers on the Blood Cells during the Delayed Asthmatic Response to Allergen Challenge." Allergy & Rhinology 5, no. 2 (January 2014): ar.2014.5.0087. http://dx.doi.org/10.2500/ar.2014.5.0087.
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Patients with bronchial asthma develop various types of asthmatic response to bronchial challenge with allergen, such as immediate/early asthmatic response (IAR), late asthmatic response (LAR) or delayed asthmatic response (DYAR), because of different immunologic mechanisms. The DYAR, occurring between 24 and 56 hours after the bronchial allergen challenge (p < 0.01), differs from IAR and LAR in clinical as well as immunologic features. This study investigates the expression of CD molecules (markers) on the surface of particular cell populations in the peripheral blood and their changes during the DYAR. In 17 patients developing the DYAR (p < 0.01), the bronchial challenge with allergen was repeated 2–6 weeks later. The repeated DYAR (p < 0.001) was combined with recording of CD molecule expression on various types of blood cells by means of flow cytometry up to 72 hours after the challenge. The results were expressed in percent of the mean relative fluorescence intensity. The DYAR was accompanied by (a) increased expression of CD11b, CD11b/18, CD16, CD32, CD35, CD62E, CD62L, CD64, and CD66b on neutrophils; CD203C on basophils; CD25and CD62L on eosinophils; CD14, CD16, CD64, and CD86 on monocytes; CD3, CD4, CD8, CD11a, CD18, and CD69 on lymphocytes; CD16, CD56, CD57, and CD94 on natural killer (NK) cells; and CD31, CD41, CD61, CD62P, and CD63 on thrombocytes and (b) decreased expression of CD18 and CD62L on eosinophils, CD15 on neutrophils, and CD40 on lymphocytes. These results suggest involvement of cell-mediated hypersensitivity mechanism, on participation of Th1- lymphocytes, neutrophils, monocytes, NK cells, and thrombocytes in the DYAR.
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Dooner, Gerri J., Gerald A. Colvin, Mark S. Dooner, and Peter J. Quesenberry. "Cell Cycle Related Stem Cell Gene Expression." Blood 104, no. 11 (November 16, 2004): 4155. http://dx.doi.org/10.1182/blood.v104.11.4155.4155.
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Abstract We have previously reported that marrow stem cells show changes in engraftment (Habibian, et al J Ex. Hem, 188:393–398, 1998), homing (Cerny et al., J Hematother Stem Cell Res11:913–922, 2002) and differentiation (Colvin et al., J Cell Phys199:20–31, 2004) phenotype as they transit a cytokine-driven cell cycle. mRNA and surface expression of adhesion proteins also change (Becker et al., Exp Hematol27:533–541, 1999). We have evaluated gene expression by Real-time PCR of murine lineage negative, Sca+ (Lin-Sca+) stem cells stimulated by Il-3, Il-6, Il-11 and Steel factor (at 0, 24 and 48h) and lineage negative Rhodamine low, Hoescht low (LRH) stem cells stimulated by TPO, Flt-3 and Steel at various points in cell cycle transit (0,32,40,48h). In Lin-Sca+ cells (4experiments, time 0) expression of the following genes in descending order was as follows: IKAROS, L-selectin, Pu-1, Gata-2, Pecam, Cd84, Rock-1, c-fms, FOG, Cxcr4, c-kit, Cd4. The following were either not expressed or expressed at very low levels: Il-11, Ccr4, Sdf-1, Gata-1, P-selectin and Vecam. A pattern of depressed gene expression in S-phase (24h) with subsequent recovery (48h) was seen with c-fms and c-kit. With LRH cells (2 experiments, time 0) approximate descending rank order of gene expression was Cd45r, Cd34, G-CSFR, Mac-1, GM-CSFR and Flt-3. Il7r was not detected. With cycle progression Cd34 and Sca-1 were markedly elevated while Mac-1 and c-mpl were decreased. The expression of GM-CSFR, G-CSFR, Cd45r and Cd4 showed variable fluctuation. Il-7r was negative throughout. These data show that primitive marrow stem cells express a wide variety of “hematopoietic genes”, that expression modulates with cell cycle transit and perhaps most importantly that observed changes in gene expression are reversible. This is consistent with the continuum theory of stem cell regulation.
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HOFMANN, S., T. VÖGTLE, M. BENDER, S. ROSE-JOHN, and B. NIESWANDT. "The SLAM family member CD84 is regulated by ADAM10 and calpain in platelets." Journal of Thrombosis and Haemostasis 10, no. 12 (December 2012): 2581–92. http://dx.doi.org/10.1111/jth.12013.
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Nanda, N., M. Bao, K. Clauser, and D. R. Phillips. "CD84 signaling is a novel platelet stimulatory mechanism that occurs during platelet aggregation." Journal of Thrombosis and Haemostasis 1 (July 2003): OC316. http://dx.doi.org/10.1111/j.1538-7836.2003.tb05250.x.
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Lewinsky, Hadas, Avital F. Barak, Victoria Huber, Matthias P. Kramer, Lihi Radomir, Lital Sever, Irit Orr, et al. "CD84 regulates PD-1/PD-L1 expression and function in chronic lymphocytic leukemia." Journal of Clinical Investigation 128, no. 12 (November 5, 2018): 5465–78. http://dx.doi.org/10.1172/jci96610.
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Takahashi, Tsuyoshi, Sussan Dejbakhsh-Jones, and Samuel Strober. "Analysis of CD161+ T Cells in Human Peripheral Blood." Blood 104, no. 11 (November 16, 2004): 3235. http://dx.doi.org/10.1182/blood.v104.11.3235.3235.
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Abstract CD161 (NKR-P1) is a natural killer receptor of C-type lectin superfamily found on natural killer (NK) cells. A significant number of both human CD4+ and CD8+ T cells express CD161. However, little is known about the extended phenotype or function of CD161+ T cells. Here, we analyzed this population in normal human peripheral blood by immunofluorescent staining, and multi-color flow cytometric analysis (N=15). Amongst CD4+ T cells, a mean of 22% showed intermediate staining for CD161 (CD161int) and the remainder were CD161−. Almost all the CD4+CD161int TCRαβ+ T cells had the CD45RO+ memory phenotype, and did not express the CD16 or CD56 NK markers (<5%). CD4+CD161− T cells were a mixture of CD45RO+ and CD45RA+ cells. Invariant natural killer T (NKT) cells with the Vα24+/Vβ11+ TCR are known to express CD161, but CD4+CD161int T cells contained less than 1 % of these invariant NKT cells. After in vitro stimulation with αCD3 and αCD28 mAb, CD4+CD161int T cells produced larger amounts of both Th1 and Th2 type cytokines compared with CD4+CD161− T cells, especially IFN-γ, IL-4 and IL-10. However, there was no difference in the proliferative response between CD161− and CD161int CD4+ T cells, and CD4+CD161int T cells had no suppressor functions against autologous cell proliferation. In CD8+ T cells, there were two populations that were CD161 positive. One was CD161hi (mean; 11%) and another was CD161int (mean; 9%). Almost all CD161int and CD161hi CD8+ T cells had the CD45RO+ memory phenotype, and few expressed the Vα24+/Vβ11+ TCR NKT cell marker (<1%) or CD16 (<5%). CD8+CD161hi cells contained around 15% of CD56+ and CD8+CD161int cells contained around 5% of CD56+. CD8+CD161hi T cells had decreased expression of CD8β and 40% of CD8+CD161hi T cells expressed only CD8α. Conversely, most of the CD8α+CD8β− T cells in human peripheral blood expressed CD161. After in vitro stimulation with αCD3 and αCD28 mAb, CD8+CD161hi T cells secreted no IFN-γ, TNF-α or IL-2. Both CD8+CD161− and CD8+CD161int T cells produced all three cytokines. CD8+CD161hi T cells failed to proliferate after αCD3+αCD28 stimulation, though CD8+CD161− and CD8+CD161int T cells made vigorous proliferative responses. Thus, it appeared that CD8+CD161hi T cells were anergic. This anergic state could not be reversed by addition of IL-2. CD8+CD161+ T cells had no suppressor function against autologous cell proliferation nor cytotoxicity against the NK or NKT sensitive tumor cell lines, K562 and Jurkat. In conclusion, the CD161 marker can be used to identify subsets of CD4+ and CD8+ T cells that differ in their extended phenotypes and functions. In addition, we identified a unique subset of anergic CD8+CD161hi T cells that express a memory phenotype with a low level of CD8β.