Journal articles: 'Recepteur cellule t'

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Camani, Chantal, Olivier Gavin, and Egbert Kruithof. "Cellular Degradation of Free and Inhibitor-bound Tissue-type Plasminogen Activator." Thrombosis and Haemostasis 83, no. 02 (2000): 290–96. http://dx.doi.org/10.1055/s-0037-1613801.

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SummaryThe low density lipoprotein receptor-related protein (LRP) is a multiligand clearance receptor that removes free tissue-type plasminogen activator (t-PA) or complexes of t-PA with plasminogen activator inhibitor type 1 (PAI-1) from the blood circulation or the pericellular space. Co-receptors are essential for LRP-mediated clearance of several ligands (e.g. glycosaminoglycans for thrombin/protease nexin and lipoprotein lipase, and the urokinase receptor for urokinase/PAI-1 complexes). The present study was undertaken to investigate whether LRP-mediated t-PA clearance requires a co-receptor as well.In five cell lines from different organs and species degradation of t-PA and t-PA/PAI-1 was mediated by LRP (or LRP-like receptors). No degradation of t-PA and t-PA/PAI-1 occurred in THP-1 or U-937 human monocyte-like cells, despite the presence of functional LRP. As glycosaminoglycans can bind t-PA and PAI-1 we investigated whether they are involved in t-PA/PAI-1 degradation. Pre-treatment of COS cells or HT1080 cells with chlorate, an inhibitor of glycosaminoglycan sulfation, did not decrease t-PA/PAI-1 degradation. Furthermore, CHO cells genetically deficient in glycosaminoglycans efficiently degraded t-PA/PAI-1. Thus it is unlikely that glycosaminoglycans are co-receptors for degradation of t-PA or t-PA/PAI-1.This study indicates that THP-1 and U-937 cells lack a critical component (co-receptor?) for the LRP-mediated degradation of t-PA. Abbreviations: LRP, low density lipoprotein receptor-related protein; PAI-1, plasminogen activator inhibitor type 1; RAP, receptor-associated protein; t-PA, tissue-type plasminogen activator; u-PA, urokinase; u-PAR, urokinase receptor.

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Marin, Ana V. M., Beatriz Garcillán, Anaïs Jiménez-Reinoso, Miguel Muñoz-Ruiz, Alejandro C. Briones, Edgar Fernández-Malavé, Maria J. Recio, and José R. Regueiro. "Human congenital T-cell receptor disorders." LymphoSign Journal 2, no. 1 (March 1, 2015): 3–19. http://dx.doi.org/10.14785/lpsn-2014-0012.

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Immunodeficiencies of most T-cell receptor (TCR) components (TCRID) have been reported in almost 40 patients worldwide who have also, at times, shown signs of autoimmunity. We updated their clinical, immunological, and molecular features with an emphasis on practical diagnosis, as the range of the disorder grows in complexity with new partial defects. Cellular and animal models are also reviewed and in some cases reveal their limitations for predicting TCRID immunopathology.

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Morctta, Lorenzo, Ermanno Ciccone, Silvano Ferrini, Pier Giuseppe Pelicci, Maria Cristina Mingari, Jan Zeromski, Cristina Bottino, Carlo Grossi, and Alessandro Moretta. "Molecular and Cellular Analysis of Human T Lymphocytes Expressing gammadelta T-Cell Receptor." Immunological Reviews 120, no. 1 (April 1991): 117–35. http://dx.doi.org/10.1111/j.1600-065x.1991.tb00590.x.

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Hamrouni, Abdelbasset, Anna Olsson, G. Jan Wiegers, and Andreas Villunger. "Impact of cellular lifespan on the T cell receptor repertoire." European Journal of Immunology 37, no. 7 (June 11, 2007): 1978–85. http://dx.doi.org/10.1002/eji.200636632.

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Lai, Kar Neng, Joseph C. K. Leung, Chun Chung Chow, and Clive S. Cockram. "T lymphocyte activation in euthyroid Graves' ophthalmopathy: soluble interleukin 2 receptor release, cellular interleukin 2 receptor expression and interleukin 2 production." Acta Endocrinologica 120, no. 5 (May 1989): 602–9. http://dx.doi.org/10.1530/acta.0.1200602.

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Abstract. The present study was undertaken to examine the cellular control arm of the immune response with regard to T lymphocyte proliferation in euthyroid Graves' ophthalmopathy. Twenty patients with euthyroid Graves' ophthalmopathy (7 on antithyroid drugs and 13 on no treatment) and 18 healthy controls were studied in an infection-free period. Mitogen-stimulated cellular interleukin 2 (IL2) receptor expression, soluble interleukin 2 receptor release, and interleukin 2 production, were studied in peripheral blood mononuclear cells cultured for 24 h. The cellular IL2 receptor expression and soluble IL2 receptor release did not differ between the patients and healthy controls. In contrast, IL2 production in response to pokeweed mitogen stimulation was increased in lymphocytes from patients with Graves' ophthalmopathy. The IL2 release did not correlate with the quantities of cellular and soluble IL2 receptor. The mitogen-stimulated cellular IL2 receptor expression, IL2 receptor release, and IL2 production did not differ between patients with or without carbimazole therapy. Despite a suggested role of autoreactive T cells in mediating the development and propagation of autoimmune thyroid disease, this study fails to demonstrate a defective T lymphocyte activation state in patients with Graves' ophthalmopathy during an euthyroid state.

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Clémenceau, Béatrice, Nicolas Congy-Jolivet, Géraldine Gallot, Régine Vivien, Joëlle Gaschet, Gilles Thibault, and Henri Vié. "Antibody-dependent cellular cytotoxicity (ADCC) is mediated by genetically modified antigen-specific human T lymphocytes." Blood 107, no. 12 (June 15, 2006): 4669–77. http://dx.doi.org/10.1182/blood-2005-09-3775.

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AbstractIn the context of transplantation, donor and virus-specific T-lymphocyte infusions have demonstrated the dramatic potential of T cells as immune effectors. Unfortunately, most attempts to exploit the T-cell immune system against nonviral malignancies in the syngeneic setting have been disappointing. In contrast, treatments based on monoclonal antibodies (Abs) have been clinically successful and have demonstrated the clinical relevance of several antigens as therapeutic targets and the importance of the antibody-dependent cellular cytotoxicity (ADCC) pathway. In the present study, we considered the possibility of arming specific T cells with a receptor that would enable them to mediate ADCC. After transduction with a CD16/γ receptor gene, CD4+ and CD8+ cytotoxic T lymphocytes displayed stable expression of the CD16 receptor at their surface. In the absence of Ab, CD16/γ expression did not affect the capacity of specific T lymphocytes to kill their target following “natural” T-cell receptor recognition. When tested against the autologous B-lymphoblastoid cell line (BLCL) coated with anti-CD20 mAb, the newly expressed Fc receptor enabled the T cells to kill the BLCL through ADCC. Adoptive transfer of such newly designed immune effector may be considered to increase antibody efficiency by harnessing the immune potential of T cells.

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Guedan, Sonia, Marco Ruella, and Carl H. June. "Emerging Cellular Therapies for Cancer." Annual Review of Immunology 37, no. 1 (April 26, 2019): 145–71. http://dx.doi.org/10.1146/annurev-immunol-042718-041407.

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Genetically engineered T cells are powerful new medicines, offering hope for curative responses in patients with cancer. Chimeric antigen receptor (CAR) T cells were recently approved by the US Food and Drug Administration and are poised to enter the practice of medicine for leukemia and lymphoma, demonstrating that engineered immune cells can serve as a powerful new class of cancer therapeutics. The emergence of synthetic biology approaches for cellular engineering provides a broadly expanded set of tools for programming immune cells for enhanced function. Advances in T cell engineering, genetic editing, the selection of optimal lymphocytes, and cell manufacturing have the potential to broaden T cell–based therapies and foster new applications beyond oncology, in infectious diseases, organ transplantation, and autoimmunity.

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Griffioen, Marieke, H. M. Esther van Egmond, Menno A. W. G. van der Hoorn, Renate S. Hagedoorn, Michel Kester, Roelof Willemze, J. H. Frederik Falkenburg, and Mirjam Heemskerk. "T Cell Receptor Gene Transfer to Virus-Specific T Cells for Cellular Anti-Tumor Immunotherapy." Blood 110, no. 11 (November 16, 2007): 2594. http://dx.doi.org/10.1182/blood.v110.11.2594.2594.

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Abstract Patients with relapsed hematological malignancies after allogeneic stem cell transplantation (alloSCT) can be successfully treated by donor lymphocyte infusions (DLI). Since DLI consists of a variety of T cells with different specificities, the benificial anti-leukemic effect of DLI is often accompanied by Graft-versus-Host Disease (GvHD). Genetic modification of T cells to express T cell receptors (TCR) with defined anti-tumor specificity would be an attractive strategy to specifically eradicate the malignant cells without induction of GvHD. We previously demonstrated that transfer of the minor histocompatibility antigen HA-2 specific TCR to CMV specific T cells led to the generation of T cells with dual specificity for CMV as well as HA-2. CMV and EBV specific T cells are ideal target cells for TCR gene transfer, since the majority of human individuals have high frequencies of these T cells due to latent persistence of CMV and EBV. In addition, based on their virus specificity, these T cells do not induce GvHD in an alloSCT setting, and we hypothesize that due to frequent encounter with viral antigens, TCR transferred virus specific T cells will survive for a prolonged period of time in vivo. The aim of this study is to develop a clinical grade method for the generation of TCR transduced virus specific T cells for cellular immunotherapy. CMV and EBV specific T cells were isolated from healthy individuals using pentamers in combination with clinical grade available anti-biotin magnetic beads. Isolation by pentamer-coated beads induced stimulation, expansion and efficient transduction of virus specific T cells, leading to the generation of cell lines with high frequencies of virus specific (>80%) and transduced (20–40%) T cells. T cells were transduced with multi-cistronic retroviral vectors encoding the α and β chains of the HA-2 TCR linked by an IRES or 2A-like sequence. No differences in transduction efficiency and TCR surface expression were observed between the IRES and 2A-like vectors. The transduced virus specific T cells were shown to exhibit dual specificity and tetramer staining of the introduced TCR correlated with specific lysis of target cells endogenously-expressing HA-2. Furthermore, variation in surface expression of the introduced TCR was observed between T cells with different virus specificities. T cells directed against the HLA-A1 epitope of CMV-pp50, for example, efficiently expressed the HA-2 TCR, whereas T cells specific for the HLA-B8 epitope of EBV-EBNA-3A did not express the introduced TCR. Functional analyses demonstrated that TCR-transduced pp50 specific T cells were dual specific, recognizing HA-2 as well as pp50 positive target cells, whereas TCR-engineered EBNA-3A specific T cells were primarily EBNA-3A specific. The efficiency of surface expression of the transferred TCR was shown to be determined by intrinsic properties of the TCRs, illustrating that for TCR gene transfer purposes TCRs need to be selected that exhibit high competition potential, whereas recipient T cells need to express endogenous TCRs with low competition potential. For clinical application, TCRs will be transferred to virus specific T cells selected for their capacity to efficiently express the introduced TCR without loss of virus specificity. The safety, clinical and immunological efficacy of TCR gene transfer to virus specific T cells as cellular anti-tumor immunotherapy after alloSCT will be investigated in a clinical phase I/II study.

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Ittershagen, Stacie, Solveig Ericson, Lamis Eldjerou, Ali Shojaee, Eric Bleickardt, Manisha Patel, Tetiana Taran, et al. "Industry’s Giant Leap Into Cellular Therapy: Catalyzing Chimeric Antigen Receptor T Cell (CAR-T) Immunotherapy." Current Hematologic Malignancy Reports 14, no. 1 (January 21, 2019): 47–55. http://dx.doi.org/10.1007/s11899-019-0498-6.

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10

Currie, James, Mario Castro, Grant Lythe, Ed Palmer, and Carmen Molina-París. "A stochastic T cell response criterion." Journal of The Royal Society Interface 9, no. 76 (June 28, 2012): 2856–70. http://dx.doi.org/10.1098/rsif.2012.0205.

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The adaptive immune system relies on different cell types to provide fast and coordinated responses, characterized by recognition of pathogenic challenge, extensive cellular proliferation and differentiation, as well as death. T cells are a subset of the adaptive immune cellular pool that recognize immunogenic peptides expressed on the surface of antigen-presenting cells by means of specialized receptors on their membrane. T cell receptor binding to ligand determines T cell responses at different times and locations during the life of a T cell. Current experimental evidence provides support to the following: (i) sufficiently long receptor–ligand engagements are required to initiate the T cell signalling cascade that results in productive signal transduction and (ii) counting devices are at work in T cells to allow signal accumulation, decoding and translation into biological responses. In the light of these results, we explore, with mathematical models, the timescales associated with T cell responses. We consider two different criteria: a stochastic one (the mean time it takes to have had N receptor–ligand complexes bound for at least a dwell time, τ , each) and one based on equilibrium (the time to reach a threshold number N of receptor–ligand complexes). We have applied mathematical models to previous experiments in the context of thymic negative selection and to recent two-dimensional experiments. Our results indicate that the stochastic criterion provides support to the thymic affinity threshold hypothesis, whereas the equilibrium one does not, and agrees with the ligand hierarchy experimentally established for thymic negative selection.

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11

Chau, Hien, Veronica Wong, Nien-Jung Chen, Huey-Lan Huang, Wen-Jye Lin, Christine Mirtsos, Alisha R. Elford, et al. "Cellular FLICE-inhibitory protein is required for T cell survival and cycling." Journal of Experimental Medicine 202, no. 3 (July 25, 2005): 405–13. http://dx.doi.org/10.1084/jem.20050118.

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Fas-associated death domain (FADD) and caspase-8 are key signal transducers for death receptor–induced apoptosis, whereas cellular FLICE-inhibitory protein (cFLIP) antagonizes this process. Interestingly, FADD and caspase-8 also play a role in T cell development and T cell receptor (TCR)–mediated proliferative responses. To investigate the underlying mechanism, we generated cFLIP-deficient T cells by reconstituting Rag−/− blastocysts with cFLIP-deficient embryonic stem cells. These Rag chimeric mutant mice (rcFLIP−/−) had severely reduced numbers of T cells in the thymus, lymph nodes, and spleen, although mature T lymphocytes did develop. Similar to FADD- or caspase-8–deficient cells, rcFLIP−/− T cells were impaired in proliferation in response to TCR stimulation. Further investigation revealed that cFLIP is required for T cell survival, as well as T cell cycling in response to TCR stimulation. Interestingly, some signaling pathways from the TCR complex appeared competent, as CD3 plus CD28 cross-linking was capable of activating the ERK pathway in rcFLIP−/− T cells. We demonstrate an essential role for cFLIP in T cell function.

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Malcolm, Tim I. M., Daniel J. Hodson, Elizabeth A. Macintyre, and Suzanne D. Turner. "Challenging perspectives on the cellular origins of lymphoma." Open Biology 6, no. 9 (September 2016): 160232. http://dx.doi.org/10.1098/rsob.160232.

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Both B and T lymphocytes have signature traits that set them apart from other cell types. They actively and repeatedly rearrange their DNA in order to produce a unique and functional antigen receptor, they have potential for massive clonal expansion upon encountering antigen via this receptor or its precursor, and they have the capacity to be extremely long lived as ‘memory’ cells. All three of these traits are fundamental to their ability to function as the adaptive immune response to infectious agents, but concurrently render these cells vulnerable to transformation. Thus, it is classically considered that lymphomas arise at a relatively late stage in a lymphocyte's development during the process of modifying diversity within antigen receptors, and when the cell is capable of responding to stimulus via its receptor. Attempts to understand the aetiology of lymphoma have reinforced this notion, as the most notable advances to date have shown chronic stimulation of the antigen receptor by infectious agents or self-antigens to be key drivers of these diseases. Despite this, there is still uncertainty about the cell of origin in some lymphomas, and increasing evidence that a subset arises in a more immature cell. Specifically, a recent study indicates that T-cell lymphoma, in particular nucleophosmin-anaplastic lymphoma kinase-driven anaplastic large cell lymphoma, may originate in T-cell progenitors in the thymus.

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Catros, Véronique. "Les CAR-T cells, des cellules tueuses spécifiques d’antigènes tumoraux." médecine/sciences 35, no. 4 (April 2019): 316–26. http://dx.doi.org/10.1051/medsci/2019067.

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Les lymphocytes T présentent des fonctions lytiques puissantes et leur adressage spécifique aux cellules tumorales afin de les détruire est un enjeu majeur. Leur ingénierie par transfert d’une construction génétique codant un fragment d’anticorps spécifique de la molécule CD19, exprimée par les lymphocytes B, fusionné à une unité de transduction d’un signal T a conduit à des résultats cliniques importants dans des formes avancées de lymphomes. Ces lymphocytes T modifiés, appelés CAR-T cells, ou plus simplement CAR pour chimeric antigen receptor, ont reçu une approbation par la Food and drug administration américaine en 2017 pour les deux premiers médicaments de thérapie cellulaire : le Kymriah™ et le Yescarta™. Ces CAR, conçus pour le traitement d’hémopathies malignes, permettent d’envisager la construction d’autres CAR dirigés, eux, contre des tumeurs solides. De nouvelles générations de CAR visent à mieux contrôler leur prolifération et à améliorer leurs fonctions in vivo grâce à la mise en place de mécanismes d’inactivation inductibles. Le développement des multi-CAR, des CAR spécifiques de plusieurs cibles, et leur combinaison aux inhibiteurs de points de contrôle immunitaires ouvrent une nouvelle ère pour l’immunothérapie des tumeurs.

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van Loenen, M. M., M. Griffioen, H. M. E. van Egmond, R. S. Hagedoorn, M. Kester, R. Willemze, J. H. F. Falkenburg, and M. H. M. Heemskerk. "338: T Cell Receptor Gene Transfer to Virus-Specific T Cells for Cellular Anti-Tumor Immunotherapy." Biology of Blood and Marrow Transplantation 14, no. 2 (February 2008): 124. http://dx.doi.org/10.1016/j.bbmt.2007.12.348.

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Gardner, Thomas J., Christopher M. Bourne, Megan M. Dacek, Keifer Kurtz, Manish Malviya, Leila Peraro, Pedro C. Silberman, et al. "Targeted Cellular Micropharmacies: Cells Engineered for Localized Drug Delivery." Cancers 12, no. 8 (August 5, 2020): 2175. http://dx.doi.org/10.3390/cancers12082175.

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The recent emergence of engineered cellular therapies, such as Chimeric antigen receptor (CAR) CAR T and T cell receptor (TCR) engineered T cells, has shown great promise in the treatment of various cancers. These agents aggregate and expand exponentially at the tumor site, resulting in potent immune activation and tumor clearance. Moreover, the ability to elaborate these cells with therapeutic agents, such as antibodies, enzymes, and immunostimulatory molecules, presents an unprecedented opportunity to specifically modulate the tumor microenvironment through cell-mediated drug delivery. This unique pharmacology, combined with significant advances in synthetic biology and cell engineering, has established a new paradigm for cells as vectors for drug delivery. Targeted cellular micropharmacies (TCMs) are a revolutionary new class of living drugs, which we envision will play an important role in cancer medicine and beyond. Here, we review important advances and considerations underway in developing this promising advancement in biological therapeutics.

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Killian, M. Scott, Jose Matud, Roger Detels, Janis V. Giorgi, and Beth D. Jamieson. "MaGiK Method of T-Cell Receptor Repertoire Analysis." Clinical and Vaccine Immunology 9, no. 4 (July 2002): 858–63. http://dx.doi.org/10.1128/cdli.9.4.858-863.2002.

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ABSTRACT T-cell receptor diversity enables the cellular immune response to recognize a broad range of viral and other pathogenic agents. An increasingly common method of characterizing T-cell receptor diversity and usage in response to antigenic challenges involves the identification of clonal expansions by PCR amplification of the CDR3 region of distinct TCRVβ families. Though clonal expansions often appear evident upon visual inspection of the results, a systematic method is needed for the valid enumeration of these expansions. Here, we describe a novel analysis method, termed the MaGiK method, for systematically identifying and enumerating clonal T-cell expansions and for applying the results to investigations of the T-cell receptor repertoire.

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Manolios, Nicholas, Marina Ali, and Vera Bender. "T-cell antigen receptor (TCR) transmembrane peptides." Cell Adhesion & Migration 4, no. 2 (April 2010): 273–83. http://dx.doi.org/10.4161/cam.4.2.11909.

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Hui, King Lam, and Arpita Upadhyaya. "Dynamic microtubules regulate cellular contractility during T-cell activation." Proceedings of the National Academy of Sciences 114, no. 21 (May 10, 2017): E4175—E4183. http://dx.doi.org/10.1073/pnas.1614291114.

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T-cell receptor (TCR) triggering and subsequent T-cell activation are essential for the adaptive immune response. Recently, multiple lines of evidence have shown that force transduction across the TCR complex is involved during TCR triggering, and that the T cell might use its force-generation machinery to probe the mechanical properties of the opposing antigen-presenting cell, giving rise to different signaling and physiological responses. Mechanistically, actin polymerization and turnover have been shown to be essential for force generation by T cells, but how these actin dynamics are regulated spatiotemporally remains poorly understood. Here, we report that traction forces generated by T cells are regulated by dynamic microtubules (MTs) at the interface. These MTs suppress Rho activation, nonmuscle myosin II bipolar filament assembly, and actin retrograde flow at the T-cell–substrate interface. Our results suggest a novel role of the MT cytoskeleton in regulating force generation during T-cell activation.

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Tang, Lu, Yinqiang Zhang, Yu Hu, and Heng Mei. "T Cell Exhaustion and CAR-T Immunotherapy in Hematological Malignancies." BioMed Research International 2021 (February 25, 2021): 1–8. http://dx.doi.org/10.1155/2021/6616391.

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T cell exhaustion has been recognized to play an immunosuppressive role in malignant diseases. Persistent tumor antigen stimulation, the presence of inhibitory immune cells and cytokines in tumor microenvironment (TME), upregulated expression of inhibitory receptors, changes in T cell-related transcription factors, and metabolic factors can all result in T cell exhaustion. Strategies dedicated to preventing or reversing T cell exhaustion are required to reduce the morbidity from cancer and enhance the effectiveness of adoptive cellular immunotherapy. Here, we summarize the current findings of T cell exhaustion in hematological malignancies and chimeric antigen receptor T (CAR-T) immunotherapy, as well as the value of novel technologies, to inverse such dysfunction. Our emerging understanding of T cell exhaustion may be utilized to develop personalized strategies to restore antitumor immunity.

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Bear, Adham S., Joseph A. Fraietta, Vivek K. Narayan, Mark O’Hara, and Naomi B. Haas. "Adoptive Cellular Therapy for Solid Tumors." American Society of Clinical Oncology Educational Book, no. 41 (March 2021): 57–65. http://dx.doi.org/10.1200/edbk_321115.

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Cancer immunotherapy tools include antibodies, vaccines, cytokines, oncolytic viruses, bispecific molecules, and cellular therapies. This review will focus on adoptive cellular therapy, which involves the isolation of a patient’s own immune cells followed by their ex vivo expansion and reinfusion. The majority of adoptive cellular therapy strategies utilize T cells isolated from tumor or peripheral blood, but may utilize other immune cell subsets. T-cell therapies in the form of tumor-infiltrating lymphocytes, T-cell receptor T cells, and CAR T cells may act as “living drugs” as these infused cells expand, engraft, and persist in vivo, allowing adaptability over time and enabling durable remissions in subsets of patients. Adoptive cellular therapy has been less successful in the management of solid tumors because of poor homing, proliferation, and survival of transferred cells. Strategies are discussed, including expression of transgenes to address these hurdles. Additionally, advances in gene editing using CRISPR/Cas9 and similar technologies are described, which allow for clinically translatable gene-editing strategies to enhance the antitumor activity and to surmount the hostilities advanced by the host and the tumor. Finally, the common toxicities and approaches to mitigate these are reviewed.

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Ivica, Nikola A., and Colin M. Young. "Tracking the CAR-T Revolution: Analysis of Clinical Trials of CAR-T and TCR-T Therapies for the Treatment of Cancer (1997–2020)." Healthcare 9, no. 8 (August 19, 2021): 1062. http://dx.doi.org/10.3390/healthcare9081062.

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Chimeric antigen receptor and T-cell receptor (CAR-T/TCR-T) cellular immunotherapies have shown remarkable success in the treatment of some refractory B-cell malignancies, with potential to provide durable clinical response for other types of cancer. In this paper, we look at all available FDA CAR-T/TCR-T clinical trials for the treatment of cancer, and analyze them with respect to different disease tissues, targeted antigens, products, and originator locations. We found that 627 of 1007 registered are currently active and of those 273 (44%) originated in China and 280 (45%) in the US. Our analysis suggests that the rapid increase in the number of clinical trials is driven by the development of different CAR-T products that use a similar therapeutic approach. We coin the term bioparallels to describe such products. Our results suggest that one feature of the CAR-T/TCR-T industry may be a robust response to success and failure of competitor products.

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Lin, Wen-Ying, Hsin-Hui Wang, Yi-Wei Chen, Chun-Fu Lin, Hueng-Chuen Fan, and Yi-Yen Lee. "Gene Modified CAR-T Cellular Therapy for Hematologic Malignancies." International Journal of Molecular Sciences 21, no. 22 (November 17, 2020): 8655. http://dx.doi.org/10.3390/ijms21228655.

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With advances in the understanding of characteristics of molecules, specific antigens on the surface of hematological malignant cells were identified and multiple therapies targeting these antigens as neoplasm treatments were developed. Among them, chimeric antigen receptor (CAR) T-cell therapy, which got United States Food and Drug Administration (FDA) approval for relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) as well as for recurrent acute lymphoblastic leukemia (ALL) within the past five years, and for r/r mantle cell lymphoma (MCL) this year, represents one of the most rapidly evolving immunotherapies. Nevertheless, its applicability to other hematological malignancies, as well as its efficacy and persistence are fraught with clinical challenges. Currently, more than one thousand clinical trials in CAR T-cell therapy are ongoing and its development is changing rapidly. This review introduces the current status of CAR T-cell therapy in terms of the basic molecular aspects of CAR T-cell therapy, its application in hematological malignancies, adverse reactions during clinical use, remaining challenges, and future utilization.

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Chiu, Ya-Hui, Jayanthi Jayawardena, Angela Weiss, Daniel Lee, Se-Ho Park, Alice Dautry-Varsat, and Albert Bendelac. "Distinct Subsets of CD1d-restricted T Cells Recognize Self-antigens Loaded in Different Cellular Compartments." Journal of Experimental Medicine 189, no. 1 (January 4, 1999): 103–10. http://dx.doi.org/10.1084/jem.189.1.103.

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Although recent studies have indicated that the major histocompatibility complex–like, β2-microglobulin–associated CD1 molecules might function to present a novel chemical class of antigens, lipids and glycolipids, to α/β T cells, little is known about the T cell subsets that interact with CD1. A subset of CD1d-autoreactive, natural killer (NK)1.1 receptor–expressing α/β T cells has recently been identified. These cells, which include both CD4−CD8− and CD4+ T cells, preferentially use an invariant Vα14-Jα281 T cell receptor (TCR) α chain paired with a Vβ8 TCR β chain in mice, or the homologous Vα24-JαQ/Vβ11 in humans. This cell subset can explosively release key cytokines such as interleukin (IL)-4 and interferon (IFN)-γ upon TCR engagement and may regulate a variety of infectious and autoimmune conditions. Here, we report the existence of a second subset of CD1d-restricted CD4+ T cells that do not express the NK1.1 receptor or the Vα14 TCR. Like the Vα14+ NK1.1+ T cells, these T cells exhibit a high frequency of autoreactivity to CD1d, use a restricted albeit distinct set of TCR gene families, and contribute to the early burst of IL-4 and IFN-γ induced by intravenous injection of anti-CD3. However, the Vα14+ NK1.1+ and Vα14− NK1.1− T cells differ markedly in their requirements for self-antigen presentation. Antigen presentation to the Vα14+ NK1.1+ cells requires endosomal targeting of CD1d through a tail-encoded tyrosine-based motif, whereas antigen presentation to the Vα14− NK1.1− cells does not. These experiments suggest the existence of two phenotypically different subsets of CD1d-restricted T cells that survey self-antigens loaded in distinct cellular compartments.

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Simeoni, Luca, and Ivan Bogeski. "Redox regulation of T-cell receptor signaling." Biological Chemistry 396, no. 5 (May 1, 2015): 555–69. http://dx.doi.org/10.1515/hsz-2014-0312.

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Abstract T-cell receptor (TCR) triggering by antigens activates a sophisticated intracellular signaling network leading to transcriptional activation, proliferation and differentiation of T cells. These events ultimately culminate in adaptive immune responses. Over recent years it has become evident that reactive oxygen species (ROS) play an important role in T-cell activation. It is now clear that ROS are involved in the regulation of T-cell mediated physiological and pathological processes. Upon TCR triggering, T cells produce oxidants, which originate from different cellular sources. In addition, within inflamed tissues, T cells are exposed to exocrine ROS produced by activated phagocytes or other ROS-producing cells. Oxidative modifications can have different effects on T-cell function. Indeed, they can stimulate T-cell activation but they can be also detrimental. These opposite effects of oxidation likely depend on different factors such as ROS concentration and source and also on the differentiation status of the T cells. Despite the well-stablished fact that ROS represent important modulators of T-cell activation, the precise molecular mechanisms of their action are far from clear. Here, we summarize the present knowledge on redox regulation of T-cell function with a particular emphasis on the redox regulation of TCR signaling.

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Lee, Sun-Hwa, Young-Hwa Chung, Nam-Hyuk Cho, Yousang Gwack, Pinghui Feng, and Jae U. Jung. "Modulation of T-Cell Receptor Signal Transduction by Herpesvirus Signaling Adaptor Protein." Molecular and Cellular Biology 24, no. 12 (June 15, 2004): 5369–82. http://dx.doi.org/10.1128/mcb.24.12.5369-5382.2004.

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ABSTRACT Because of its central regulatory role, T-cell receptor (TCR) signal transduction is a common target of viruses. We report here the identification of a small signaling protein, ORF5, of the T-lymphotropic tumor virus herpesvirus saimiri (HVS). ORF5 is predicted to contain 89 to 91 amino acids with an amino-terminal myristoylation site and six SH2 binding motifs, showing structural similarity to cellular LAT (linker for activation of T cells). Sequence analysis showed that, despite extensive sequence variation, the myristoylation site and SH2 binding motifs were completely conserved among 13 different ORF5 isolates. Upon TCR stimulation, ORF5 was efficiently tyrosine phosphorylated and subsequently interacted with cellular SH2-containing signaling proteins Lck, Fyn, SLP-76, and p85 through its tyrosine residues. ORF5 expression resulted in the marked augmentation of TCR signal transduction activity, evidenced by increased cellular tyrosine phosphorylation, intracellular calcium mobilization, CD69 surface expression, interleukin-2 production, and activation of the NF-AT, NF-κB, and AP-1 transcription factors. Despite its structural similarity to cellular LAT, however, ORF5 could only partially substitute for LAT function in TCR signal transduction. These results demonstrate that HVS utilizes a novel signaling protein, ORF5, to activate TCR signal transduction. This activation probably facilitates viral gene expression and, thereby, persistent infection.

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Collenburg, Lena, Sibylle Schneider-Schaulies, and Elita Avota. "The neutral sphingomyelinase 2 in T cell receptor signaling and polarity." Biological Chemistry 399, no. 10 (September 25, 2018): 1147–55. http://dx.doi.org/10.1515/hsz-2017-0280.

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AbstractBy hydrolyzing its substrate sphingomyelin at the cytosolic leaflet of cellular membranes, the neutral sphingomyelinase 2 (NSM2) generates microdomains which serve as docking sites for signaling proteins and thereby, functions to regulate signal relay. This has been particularly studied in cellular stress responses while the regulatory role of this enzyme in the immune cell compartment has only recently emerged. In T cells, phenotypic polarization by co-ordinated cytoskeletal remodeling is central to motility and interaction with endothelial or antigen-presenting cells during tissue recruitment or immune synapse formation, respectively. This review highlights studies adressing the role of NSM2 in T cell polarity in which the enzyme plays a major role in regulating cytoskeletal dynamics.

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Stein, Andrew M., Stephan A. Grupp, John E. Levine, Theodore W. Laetsch, Michael A. Pulsipher, Michael W. Boyer, Keith J. August, et al. "Tisagenlecleucel Model‐Based Cellular Kinetic Analysis of Chimeric Antigen Receptor–T Cells." CPT: Pharmacometrics & Systems Pharmacology 8, no. 5 (March 7, 2019): 285–95. http://dx.doi.org/10.1002/psp4.12388.

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Mangan, P. "Cellular Immunotherapy for Myeloma using Chimeric Antigen Receptor Modified T Cells (CARs)." Clinical Lymphoma Myeloma and Leukemia 15 (September 2015): e319. http://dx.doi.org/10.1016/j.clml.2015.08.094.

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Tyagarajan, Seshu, David Schmitt, Christopher Acker, and Erik Rutjens. "Autologous cryopreserved leukapheresis cellular material for chimeric antigen receptor–T cell manufacture." Cytotherapy 21, no. 12 (December 2019): 1198–205. http://dx.doi.org/10.1016/j.jcyt.2019.10.005.

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Bonini, Chiara. "Engineering T-Cells Beyond Chimeric Antigen Receptor." Blood 128, no. 22 (December 2, 2016): SCI—13—SCI—13. http://dx.doi.org/10.1182/blood.v128.22.sci-13.sci-13.

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Adoptive T cell therapy exploits the ability of T lymphocytes to recognize and destroy specific targets, on microbes or tumors, through their T cell receptors (TCR), leading to efficient killing and long-term protection against diseases. Unfortunately, tumor antigens are often overexpressed, unmodified self-antigens, subject to tolerance mechanisms; so tumor-specific T lymphocytes are rare cells. Conversely, neoantigens derive from oncogenic mutations can elicit productive T cell responses, but for tumors with a low mutational load, such as the majority of hematological malignancies, such tumor-specific T cells are rarely identified. These limitations can be overcome by genetic engineering of T lymphocyte specificity. Recently, unprecedented clinical results were obtained with chimeric antigen receptor (CAR) engineered T cells in patients affected by B-cell malignancies, raising high expectations among the scientific community, patient associations, biotech companies and general public. While clearly proving the ability of redirected T cells to recognize and efficiently kill cancer cells, CAR therapy has also shown some limitations: the nature of CAR-mediated recognition imposes to restrict the array of targeted antigens to those expressed on the surface of cancer cells. As a consequence, antigens involved in the oncogenic process, that are often expressed as intracellular molecules, cannot be targeted by current CARs. Furthermore, when the natural counterpart of cancer cells cannot be spared, the identification of a proper CAR target on cancer cell surface might become a real challenge. TCR genetic engineering represents a suitable alternative to CAR T cell therapy for several tumors. The core of this approach is the transfer in patients' T cells of genes encoding for rare tumor-specific TCR. TCRs recognize antigen-derived peptides processed and presented on HLA molecules, thus allowing to largely increasing the array of potential targets. However, the simple transfer of tumor specific TCR genes into T cells is affected by other limitations: genetically modified T cells shall express four different TCR chains, that might mispair, leading to unpredictable toxicity and to an overall dilution of the tumor specific TCR on lymphocyte surface, thus limiting the efficacy of therapeutic cellular product. To overcome these issues, we developed a TCR gene editing procedure, based on the knockout of the endogenous TCR genes by transient exposure to alfa and beta chain specific Zinc Finger Nucleases (ZFNs), followed by the introduction of tumor-specific TCR genes by lentiviral vectors (Provasi et al, Nature Medicine 2012). The TCR gene editing technology, proved safer and more effective than conventional TCR gene transfer in vitro and in animal studies. Early differentiated T cells, such as memory stem T cells and central memory T cells, cells endowed with long term persistence capacity, can be genetically engineered by TCR gene transfer and TCR gene editing, thus allowing to produce long-lasting living drugs, with the aim of eliminating cancer cells and patrol the organism for tumor recurrence To enter the phase of clinical practice adoptive T cell therapy needs today to face several challenges: compliance to the dynamic and heterogeneous regulatory framework, susceptibility to automated processes, reproducibility, and sustainability shall be relevant variables in determining the fate of these innovative cellular products. Disclosures Bonini: TxCell: Membership on an entity's Board of Directors or advisory committees; Molmed SpA: Consultancy.

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Sobel, E. S. "Cellular Interactions in the LPR and GLD Models of Systemic Autoimmunity." Advances in Dental Research 10, no. 1 (April 1996): 76–80. http://dx.doi.org/10.1177/08959374960100011601.

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The lpr and gld murine models have been important contributors to our understanding of systemic autoimmune diseases. Mice homozygous for either of these autosomal recessive genes develop a phenotypically identical disease characterized by the accumulation of CD4-CD8- T-cells and the production of a wide spectrum of autoantibodies. The lpr (lymphoproliferation) mutation encodes a defective Fas apoptosis receptor gene. More recently, gld (generalized lymphadenopathy) has been shown to be a point mutation in the Fas ligand gene. Despite the molecular characterization of these mutations, the exact mechanism by which tolerance is lost is still unknown, although in vivo cell transfer studies have provided clues. Chimera studies, in which normal and lpr bone marrow were co-infused into lpr mice, demonstrated not only that the normal Fas receptor is functionally expressed in both T- and B-cells, but that the Fas mutation is required in both for full expression of the lpr phenotype. Conversely, in analogous experiments with gld mice, co-infusion of normal and gld bone marrow largely prevented the development of autoantibodies. Sporadic autoantibody titers were seen in some mice, but were derived from both donors. The effects on T-cells were subtly different: The CD4-CD8- T-cells were also greatly reduced in number, but all were of gld origin. These data indicate that the gld defect is extrinsic to B-cells but only partially extrinsic to T-cells, and suggest that Fas ligand in T-cells may have an autocrine and paracrine function.

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Verdon, Daniel J., Matthias Mulazzani, and Misty R. Jenkins. "Cellular and Molecular Mechanisms of CD8+ T Cell Differentiation, Dysfunction and Exhaustion." International Journal of Molecular Sciences 21, no. 19 (October 5, 2020): 7357. http://dx.doi.org/10.3390/ijms21197357.

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T cells follow a triphasic distinct pathway of activation, proliferation and differentiation before becoming functionally and phenotypically “exhausted” in settings of chronic infection, autoimmunity and in cancer. Exhausted T cells progressively lose canonical effector functions, exhibit altered transcriptional networks and epigenetic signatures and gain constitutive expression of a broad coinhibitory receptor suite. This review outlines recent advances in our understanding of exhausted T cell biology and examines cellular and molecular mechanisms by which a state of dysfunction or exhaustion is established, and mechanisms by which exhausted T cells may still contribute to pathogen or tumour control. Further, this review describes our understanding of exhausted T cell heterogeneity and outlines the mechanisms by which checkpoint blockade differentially engages exhausted T cell subsets to overcome exhaustion and recover T cell function.

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Oppermans, Natasha, Gray Kueberuwa, Robert E. Hawkins, and John S. Bridgeman. "Transgenic T-cell receptor immunotherapy for cancer: building on clinical success." Therapeutic Advances in Vaccines and Immunotherapy 8 (January 2020): 251513552093350. http://dx.doi.org/10.1177/2515135520933509.

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With the advent of immunotherapy as a realistic and promising option for cancer treatment, adoptive cellular therapies are gaining significant interest in the clinic. Whilst the recent successes of chimeric antigen receptor T-cell therapies for haematological malignancies are widely known, they have yet to show great success in solid cancers. However, immune cells transduced with T-cell receptors have been shown to traffic to and exert anti-cancer effects on solid tumour cells with some great successes. In this review, we explore the field of transgenic T-cell receptor immunotherapy, highlighting some of the key clinical trials which have paved the way for this type of cellular immunotherapy. Some trials have shown amazing clinical results, including long-term remissions and minimal toxicity, and can be looked at as an exemplar for this adoptive cell therapy. There have also been key trials where unexpected, fatal, off-tumour toxicity has occurred, and these trials have also been instrumental in shaping safer clinical trials, particularly regarding preclinical testing. In addition to previous trials, we analysed the current clinical trial space for T-cell receptor T-cell therapy, showing which trials are dominating in the clinic and which targets are being prioritised by researchers around the world. By looking at both past and current trials, we have been able to identify key drivers in developing transgenic T-cell receptor immunotherapy for the future.

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Scott, Anthony, and Zhenghe Wang. "Tumour suppressor function of protein tyrosine phosphatase receptor-T." Bioscience Reports 31, no. 5 (April 21, 2011): 303–7. http://dx.doi.org/10.1042/bsr20100134.

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It has long been thought that PTPs (protein tyrosine phosphatases) normally function as tumour suppressors. Recent high-throughput mutational analysis identified loss-of-function mutations in six PTPs in human colon cancers, providing critical cancer genetics evidence that PTPs can act as tumour suppressor genes. PTPRT (protein tyrosine phosphatase receptor-T), a member of the family of type IIB receptor-like PTPs, is the most frequently mutated PTP among them. Consistent with the notion that PTPRT is a tumour suppressor, PTPRT knockout mice are hypersensitive to AOM (azoxymethane)-induced colon cancer. The present review focuses on the physiological and pathological functions of PTPRT as well as the cellular pathways regulated by this phosphatase.

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Kuwabara, Soichiro, Yoshihiko Tanimoto, Mie Okutani, Meng Jie, Yasunari Haseda, Yumi Kinugasa-Katayama, and Taiki Aoshi. "Microfluidics sorting enables the isolation of an intact cellular pair complex of CD8+ T cells and antigen-presenting cells in a cognate antigen recognition-dependent manner." PLOS ONE 16, no. 6 (June 14, 2021): e0252666. http://dx.doi.org/10.1371/journal.pone.0252666.

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Adaptive immune responses begin with cognate antigen presentation-dependent specific interaction between T cells and antigen-presenting cells. However, there have been limited reports on the isolation and analysis of these cellular complexes of T cell-antigen-presenting cell (T/APC). In this study, we successfully isolated intact antigen-specific cellular complexes of CD8+ T/APC by utilizing a microfluidics cell sorter. Using ovalbumin (OVA) model antigen and OT-I-derived OVA-specific CD8+ T cells, we analyzed the formation of antigen-specific and antigen-non-specific T/APC cellular complexes and revealed that the antigen-specific T/APC cellular complex was highly stable than the non-specific one, and that the intact antigen-specific T/APC complex can be retrieved as well as enriched using a microfluidics sorter, but not a conventional cell sorter. The single T/APC cellular complex obtained can be further analyzed for the sequences of T cell receptor Vα and Vβ genes as well as cognate antigen information simultaneously. These results suggested that this approach can be applied for other antigen and CD8+ T cells of mice and possibly those of humans. We believe that this microfluidics sorting method of the T/APC complex will provide useful information for future T cell immunology research.

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Schindler, Marcus, Kathleen A. Harrington, Patrick P. A. Humphrey, and Piers C. Emson. "Cellular localisation and co-expression of somatostatin receptor messenger RNAs in the human brain." Molecular Brain Research 34, no. 2 (December 1995): 321–26. http://dx.doi.org/10.1016/0169-328x(95)00191-t.

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Mulle, Christophe, Daniel Choquet, Henri Korn, and Jean-Pierre Changeux. "Calcium influx through nicotinic receptor in rat central neurons: Its relevance to cellular regulation." Neuron 8, no. 1 (January 1992): 135–43. http://dx.doi.org/10.1016/0896-6273(92)90115-t.

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38

Barrett-Bergshoeff, Marrie, Femke Noorman, Rogier Bos, and Dingeman C. Rijken. "Monoclonal Antibodies against the Human Mannose Receptor that Inhibit the Binding of Tissue-type Plasminogen Activator." Thrombosis and Haemostasis 77, no. 04 (1997): 718–24. http://dx.doi.org/10.1055/s-0038-1656040.

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SummaryTo study the role of the mannose receptor in cellular uptake and degradation of tissue-type plasminogen activator (t-PA), a set of five monoclonal antibodies (Moab) was generated against the mannose receptor isolated from human placental tissue.All Moab specifically recognised the 175 kDa mannose receptor in a crude placenta extract, as shown in Western blot analysis. By use of im- munohistochemistry, we showed that in human placenta only the Hof- bauer cells (fetal macrophages) express the mannose receptor. Epitope competition experiments indicated that the Moab bound to at least two different epitopes on the receptor molecule. Moab 14-3, 14-5, and 15-2, which are directed against one of these epitopes, strongly inhibited the interaction between the purified mannose receptor and t-PA. These Moab also inhibited mannose receptor-mediated degradation of t-PA by cultured human macrophages. The low density lipoprotein receptor-related protein (LRP) mediated t-PA degradation was not affected by the Moab.It is concluded that the Moab are useful for studying the expression of the human mannose receptor in Western blot and in immunohisto-chemistry, and for studying the interactions between the human mannose receptor and the mannose-containing ligand t-PA.

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39

Addissie, Selamawit, and Hans Klingemann. "Cellular Immunotherapy of Canine Cancer." Veterinary Sciences 5, no. 4 (December 6, 2018): 100. http://dx.doi.org/10.3390/vetsci5040100.

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Infusions with immune cells, such as lymphocytes or natural killer (NK) cells, represent one of several modalities of immunotherapy. In human patients with advanced B-cell leukemia or lymphoma, infusions with chimeric antigen receptor (CAR) T-lymphocytes have shown promising responses. However, the scientific and clinical development of cell-based therapies for dogs, who get cancer of similar types as humans, is lagging behind. One reason is that immune cells and their functionality in dogs are less well characterized, largely due a lack of canine-specific reagents to detect surface markers, and specific cytokines to isolate and expand their immune cells. This review summarizes the current status of canine cancer immunotherapies, with focus on autologous and allogeneic T-lymphocytes, as well as NK cells, and discusses potential initiatives that would allow therapies with canine immune cells to “catch up” with the advances in humans.

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40

Duhrsen, U., M. Uppenkamp, I. Uppenkamp, R. Becher, M. Engelhard, E. Konig, P. Meusers, S. Meuer, and G. Brittinger. "Chronic T cell leukemia with unusual cellular characteristics in ataxia telangiectasia." Blood 68, no. 2 (August 1, 1986): 577–85. http://dx.doi.org/10.1182/blood.v68.2.577.577.

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Abstract A 27-year-old male patient with ataxia telangiectasia (AT) developed atypical chronic lymphocytic leukemia with increasing bone marrow infiltration in the absence of organomegaly. One-third of the leukemia cells expressed a mature suppressor/cytotoxic T cell phenotype (T3+ T4- T6- T8+ T10-), two-thirds demonstrated additional helper/inducer T cell- associated antigens (T3+ T4+ T6- T8+ T10-), and a small fraction reacted with a natural killer (NK) cell-specific monoclonal antibody (Leu 11+). The proliferative response to stimulation in vitro with lectins and various monoclonal antibodies resembled the proliferation pattern of mature thymocytes: The cells responded to phytohemagglutinin (PHA), concanavalin A (ConA), stimulation of the T3-Ti receptor complex with Sepharose-bound anti-T3, and stimulation of the sheep erythrocyte receptor protein with anti-T11(2) and anti-T11(3) in conjunction with exogenous interleukin-2 (IL 2); they failed, however, to proliferate after stimulation with anti-T11(2) and anti-T11(3) alone. There was no response in the mixed lymphocyte reaction (MLR) and no suppression of the MLR between two healthy donors. Antibody-dependent cell-mediated cytotoxicity and NK activity could not be demonstrated. Cytogenetic analysis revealed complex clonal aberrations, including an interstitial deletion of the long arm of chromosome 14 concerning bands q21–31, loss of chromosome 20, and loss of the Y chromosome. Cytostatic chemotherapy was of little use and caused serious side effects, whereas leukapheresis proved effective in reducing the tumor load. The clinical data and laboratory findings in this case correspond to three previously described patients with AT who developed chronic T cell leukemia. Thus, in adult patients with AT, malignant proliferation of cytogenetically marked and phenotypically heterogeneous mature T cells seems to be a frequent complication.

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41

Duhrsen, U., M. Uppenkamp, I. Uppenkamp, R. Becher, M. Engelhard, E. Konig, P. Meusers, S. Meuer, and G. Brittinger. "Chronic T cell leukemia with unusual cellular characteristics in ataxia telangiectasia." Blood 68, no. 2 (August 1, 1986): 577–85. http://dx.doi.org/10.1182/blood.v68.2.577.bloodjournal682577.

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A 27-year-old male patient with ataxia telangiectasia (AT) developed atypical chronic lymphocytic leukemia with increasing bone marrow infiltration in the absence of organomegaly. One-third of the leukemia cells expressed a mature suppressor/cytotoxic T cell phenotype (T3+ T4- T6- T8+ T10-), two-thirds demonstrated additional helper/inducer T cell- associated antigens (T3+ T4+ T6- T8+ T10-), and a small fraction reacted with a natural killer (NK) cell-specific monoclonal antibody (Leu 11+). The proliferative response to stimulation in vitro with lectins and various monoclonal antibodies resembled the proliferation pattern of mature thymocytes: The cells responded to phytohemagglutinin (PHA), concanavalin A (ConA), stimulation of the T3-Ti receptor complex with Sepharose-bound anti-T3, and stimulation of the sheep erythrocyte receptor protein with anti-T11(2) and anti-T11(3) in conjunction with exogenous interleukin-2 (IL 2); they failed, however, to proliferate after stimulation with anti-T11(2) and anti-T11(3) alone. There was no response in the mixed lymphocyte reaction (MLR) and no suppression of the MLR between two healthy donors. Antibody-dependent cell-mediated cytotoxicity and NK activity could not be demonstrated. Cytogenetic analysis revealed complex clonal aberrations, including an interstitial deletion of the long arm of chromosome 14 concerning bands q21–31, loss of chromosome 20, and loss of the Y chromosome. Cytostatic chemotherapy was of little use and caused serious side effects, whereas leukapheresis proved effective in reducing the tumor load. The clinical data and laboratory findings in this case correspond to three previously described patients with AT who developed chronic T cell leukemia. Thus, in adult patients with AT, malignant proliferation of cytogenetically marked and phenotypically heterogeneous mature T cells seems to be a frequent complication.

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Cohen, Adam D. "CAR T Cells and Other Cellular Therapies for Multiple Myeloma: 2018 Update." American Society of Clinical Oncology Educational Book, no. 38 (May 2018): e6-e15. http://dx.doi.org/10.1200/edbk_200889.

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Cellular therapies are a rapidly evolving approach to myeloma treatment, which bring a unique mechanism of action with the potential to overcome drug resistance and induce long-term remissions. Two primary approaches are being studied: non–gene-modified strategies, which rely on the endogenous anti-myeloma T-cell repertoire, and gene-modified strategies, which introduce a new T-cell receptor (TCR) or a chimeric antigen receptor (CAR) to confer novel antigen specificity. CAR T cells show the greatest activity to date. Multiple antigen targets, including B-cell maturation antigen (BCMA), CD19, CD38, CD138, and SLAMF7, are being explored for myeloma, and BCMA has emerged as the most promising. Preliminary data from four phase I studies of BCMA CAR T cells, each using a different CAR construct, that involved 90 evaluable patients with relapsed/refractory disease have been reported. These data show response rates of 60% to 100%, including minimal residual disease (MRD)-negative complete remissions, at effective doses (> 108 CAR-positive cells) after lymphodepleting conditioning. Response durability has been more variable, likely related to differences in CAR T-cell products, lymphodepleting regimens, patient selection criteria, and/or underlying biology/prognostic factors. In the two most recent studies, however, most patients remained progression free with median follow-up time of 6 to 10 months; some ongoing remissions lasted more than 1 year. Toxicities are similar to those from CD19 CAR T cells and include cytokine release syndrome and neurotoxicity that is reversible but can be severe. Multiple BCMA CAR T-cell studies are ongoing. Future directions include combinations with immunomodulatory drugs, checkpoint inhibitors, or other CAR T cells, as well as use of gene-edited cellular products to enhance the safety and efficacy of this approach.

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Usuku, K., N. Joshi, C. J. Hatem, M. A. Wong, M. C. Stein, and S. L. Hauser. "Biased expression of T cell receptor genes characterizes activated T cells in multiple sclerosis cerebrospinal fluid." Journal of Neuroscience Research 45, no. 6 (September 15, 1996): 829–37. http://dx.doi.org/10.1002/(sici)1097-4547(19960915)45:6<829::aid-jnr20>3.0.co;2-p.

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Chahroudi, Ann, Rahul Chavan, Natalia Koyzr, Edmund K. Waller, Guido Silvestri, and Mark B. Feinberg. "Vaccinia Virus Tropism for Primary Hematolymphoid Cells Is Determined by Restricted Expression of a Unique Virus Receptor." Journal of Virology 79, no. 16 (August 15, 2005): 10397–407. http://dx.doi.org/10.1128/jvi.79.16.10397-10407.2005.

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ABSTRACT The presumed broad tropism of poxviruses has stymied attempts to identify both the cellular receptor(s) and the viral determinant(s) for binding. Detailed studies of poxvirus binding to and infection of primary human cells have not been conducted. In particular, the determinants of target cell infection and the consequences of infection for cells involved in the generation of antiviral immune responses are incompletely understood. In this report, we show that vaccinia virus (VV) exhibits a more restricted tropism for primary hematolymphoid human cells than has been previously recognized. We demonstrate that vaccinia virus preferentially infects antigen-presenting cells (dendritic cells, monocytes/macrophages, and B cells) and activated T cells, but not resting T cells. The infection of activated T cells is permissive, with active viral replication and production of infectious progeny. Susceptibility to infection is determined by restricted expression of a cellular receptor that is induced de novo upon T-cell activation and can be removed from the cell surface by either trypsin or pronase treatment. The VV receptor expressed on activated T cells displays unique characteristics that distinguish it from the receptor used to infect cell lines in culture. The observed restricted tropism of VV may have significant consequences for the understanding of natural poxvirus infection and immunity and for poxvirus-based vaccine development.

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Pavlakis, M., M. L. Lipman, and T. B. Strom. "Intragraft T cell receptor transcript expression in human renal allografts." Journal of the American Society of Nephrology 6, no. 2 (August 1995): 281–85. http://dx.doi.org/10.1681/asn.v62281.

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Allograft rejection is a T cell-dependent process. It is not known whether rejection is mediated by a limited number of T cell clones or by a polyclonal population of T cells. Several studies attempting to answer this question using molecular techniques to analyze the T cell receptor (TCR) population have reached conflicting conclusions. Reverse transcription-assisted polymerase chain reaction (PCR) has been used to quantify T cell infiltration and examine TCR heterogeneity in kidney transplant biopsies from patients experiencing graft dysfunction. RNA from snap-frozen biopsies gathered on 23 transplant patients was reverse transcribed to cDNA and used as the template for PCR. The constant region gene of the TCR beta chain (C beta), 22 different variable region genes of the TCR beta chain (V beta) and the constitutively expressed glyceraldehyde phosphate dehydrogenase (GAPD) gene were amplified. T cell infiltration, as estimated by the ratio of reverse-transcribed cDNA C beta/glyceraldehyde phosphate dehydrogenase, was significantly higher in acute cellular rejection (ACR) (2.25) than in nonrejection (NR) (0.40, P < 0.05). The number of intragraft V beta families was higher in chronic rejection and acute cellular rejection (18 and 16.4, respectively) than in nonrejection (8.7). Five serial biopsies from two patients progressing to immunologic graft loss showed an increase in the number of intragraft V beta families. The finding of increased numbers of TCR V beta families amplified from acutely and chronically rejecting grafts as compared with nonrejecting graft supports the hypothesis that, at the time of clinically apparent rejection, there is a polyclonal infilitration of T cells.

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Wong, David M., Vivian Tam, Roselind Lam, Katrina A. Walsh, Liliana Tatarczuch, Charles N. Pagel, Eric C. Reynolds, Neil M. O'Brien-Simpson, Eleanor J. Mackie, and Robert N. Pike. "Protease-Activated Receptor 2 Has Pivotal Roles in Cellular Mechanisms Involved in Experimental Periodontitis." Infection and Immunity 78, no. 2 (November 23, 2009): 629–38. http://dx.doi.org/10.1128/iai.01019-09.

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ABSTRACT The tissue destruction seen in chronic periodontitis is commonly accepted to involve extensive upregulation of the host inflammatory response. Protease-activated receptor 2 (PAR-2)-null mice infected with Porphyromonas gingivalis did not display periodontal bone resorption in contrast to wild-type-infected and PAR-1-null-infected mice. Histological examination of tissues confirmed the lowered bone resorption in PAR-2-null mice and identified a substantial decrease in mast cells infiltrating the periodontal tissues of these mice. T cells from P. gingivalis-infected or immunized PAR-2-null mice proliferated less in response to antigen than those from wild-type animals. CD90 (Thy1.2) expression on CD4+ and CD8+ T-cell-receptor β (TCRβ) T cells was significantly (P < 0.001) decreased in antigen-immunized PAR-2-null mice compared to sham-immunized PAR-2-null mice; this was not observed in wild-type controls. T cells from infected or antigen-immunized PAR-2-null mice had a significantly different Th1/inflammatory cytokine profile from wild-type cells: in particular, gamma interferon, interleukins (interleukin-2, -3, and -17), granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor alpha demonstrated lower expression than wild-type controls. The absence of PAR-2 therefore appears to substantially decrease T-cell activation and the Th1/inflammatory response. Regulation of such proinflammatory mechanisms in T cells and mast cells by PAR-2 suggests a pivotal role in the pathogenesis of the disease.

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Bumann, Dirk. "T cell receptor-transgenic mouse models for studying cellular immune responses toSalmonellain vivo." FEMS Immunology & Medical Microbiology 37, no. 2-3 (July 2003): 105–9. http://dx.doi.org/10.1016/s0928-8244(03)00064-6.

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Punwani, Divya, Diana Gonzalez-Espinosa, Anne Marie Comeau, Amalia Dutra, Evgenia Pak, and Jennifer Puck. "Cellular calibrators to quantitate T-cell receptor excision circles (TRECs) in clinical samples." Molecular Genetics and Metabolism 107, no. 3 (November 2012): 586–91. http://dx.doi.org/10.1016/j.ymgme.2012.09.018.

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Glik, Amir, and Amos Douvdevani. "T Lymphocytes: The “Cellular” Arm of Acquired Immunity in the Peritoneum." Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 26, no. 4 (July 2006): 438–48. http://dx.doi.org/10.1177/089686080602600407.

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T cells are an important part of the acquired immune response and target specific antigen with their T cell receptor. The peritoneum is a special milieu within which T cells react. We describe briefly the anatomy important for T cell function. T cell biology including antigen presentation, T cell activation, and the different T cell subpopulations are reviewed. We also define innate and acquired immunity and describe the role of polymorphonuclear cells and peritoneal mesothelial cells in the regulation of leukocyte population recruitment during peritonitis. We focus particularly on peritoneal lymphocytes and compare them to the regular lymphocyte populations in the circulation. We illustrate the role of PMCs in antigen presentation and discuss the changes of CD4+ helper T cell subtypes (Th1 and Th2) during peritoneal dialysis. The role of CD8+ cytotoxic T lymphocytes and their possible destructive role for the peritoneal membrane modified by advanced glycation end products are discussed. Polymorphonuclear cells play an important role in the regulation of inflammation and immunity. We describe their possible role in supporting T cells and particularly for generating memory CD8+ T cells by secretion of interleukin-15, a potent T cell growth factor. Light is shed on γδ T cells, a special T cell population that is able to recognize antigens without the restriction of antigen presentation. We end our review with a description of regulatory T cells. This cell population is extremely important in preventing autoimmunity and in the regulation of acquired immunity.

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Antonelli, Lis R. V., Walderez O. Dutra, Ricardo R. Oliveira, Karen C. L. Torres, Luiz H. Guimarães, Olivia Bacellar, and Kenneth J. Gollob. "Disparate Immunoregulatory Potentials for Double-Negative (CD4− CD8−) αβ and γδ T Cells from Human Patients with Cutaneous Leishmaniasis." Infection and Immunity 74, no. 11 (August 21, 2006): 6317–23. http://dx.doi.org/10.1128/iai.00890-06.

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ABSTRACT Although most T lymphocytes express the αβ T-cell receptor and either CD4 or CD8 molecules, a small population of cells lacking these coreceptors, CD4− CD8− (double negative [DN]) T cells, has been identified in the peripheral immune system of mice and humans. To better understand the role that this population may have in the human immune response against Leishmania spp., a detailed study defining the activation state, cytokine profile, and the heterogeneity of DN T cells bearing αβ or γδ T-cell receptors was performed with a group of well-defined cutaneous leishmaniasis patients. Strikingly, on average 75% of DN T cells from cutaneous leishmaniasis patients expressed the αβ T-cell receptor, with the remainder expressing the γδ receptor, while healthy donors displayed the opposite distribution with ∼75% of the DN T cells expressing the γδ T-cell receptor. Additionally, αβ DN T cells from cutaneous leishmaniasis patients are compatible with previous antigen exposure and recent activation. Moreover, while αβ DN T cells from Leishmania-infected individuals present a proinflammatory cytokine profile, γδ DN T cells express a regulatory profile exemplified by interleukin-10 production. The balance between these subpopulations could allow for the formation of an effective cellular response while limiting its pathogenic potential.

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Journal articles on the topic 'Recepteur cellule t'

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