Dual TCR Expression Effects on Alloreactivity and Transplantation

双重 TCR 表达对同种异体反应性和移植的影响

• 批准号: 10569602
• 负责人: Gerald Patrick Morris
• 金额: $ 38.14万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-05 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569602
• 关键词: Acute; Address; Alloantigen; Allogenic; Antigens; Autoantigens; Autoimmune Diseases; Automobile Driving; B-Lymphocytes; Biology; Cell Therapy; Cells; Cellular biology; Clinical; Complication; Data; Development; Diabetes Mellitus; Disease; Dissection; Exhibits; Frequencies; Goals; Hematopoietic Stem Cell Transplantation; Human; Hybrid Cells; Immunologics; Individual; Libraries; Life; Ligands; Link; MHC Interaction; Measures; Mediating; Modeling; Mus; Outcome; Pathologic; Patients; Peptide/MHC Complex; Peptides; Physiology; Proliferating; Property; Receptor Cell; Regulatory T-Lymphocyte; Reporter; Research; Specificity; System; T cell receptor repertoire sequencing; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; TRA@ gene cluster; Testing; Therapeutic; Thymus Gland; Transgenic Mice; Transplant Recipients; Transplantation; Variant; Work; autoreactivity; chronic graft versus host disease; cross reactivity; flexibility; graft vs host disease; improved; innovation; insight; mouse model; mutant; novel; novel strategies; receptor; receptor expression; reconstitution; response; single cell sequencing; tool

Project Summary/Abstract In normal physiology, the repertoire of human T cells includes a 10% subpopulation that expresses two, rather than a single, T cell receptor (TCR). Despite the obvious implications of dual-specificity at the clonal level, the function of this dual TCR subpopulation remains largely unknown. We recently proposed the novel paradigm and provided evidence demonstrating that naturally-arising dual TCR expression is important in thymopoiesis and that dual TCR cells have exceptional ability to recognize ligands driving alloreactivity and autoreactivity. This reactivity is relevant to disease, as we demonstrated in mouse models and human patients that dual TCR T cells are important drivers in graft versus host disease, a severe and life-threatening T cell-mediated complication of hematopoietic stem cell transplantation. Data from other models also link dual TCR T cells to autoimmune disease such as diabetes. Despite evidence of the importance of dual TCR cells, they have been understudied due to the inability to definitively identify, isolate, and functionally study T cells expressing dual TCRs. To address this, we have developed novel approaches including single-cell TCR sequencing of mouse and human cells, and transgenic mice with fluorescent reporters for TCRα. We intend that these tools will enable us to address our hypotheses and generate novel insights into fundamental TCR biology to identify potential avenues to improve clinical transplantation.

项目总结/摘要 在正常生理学中，人类T细胞的库包括10%的亚群，其表达两个，而不是两个。 T细胞受体（TCR）。尽管在克隆水平上具有明显的双重特异性， 这种双重TCR亚群的功能在很大程度上仍然未知。我们最近提出了一种新的范式， 并提供证据证明天然产生的双TCR表达在胸腺生成中是重要的 并且双TCR细胞具有识别驱动同种异体反应性和自身反应性的配体的特殊能力。这 正如我们在小鼠模型和人类患者中证明的那样，双TCR T细胞 是移植物抗宿主病的重要驱动因素，移植物抗宿主病是一种严重的和危及生命的T细胞介导的并发症， 造血干细胞移植来自其他模型的数据也将双重TCR T细胞与自身免疫性疾病联系起来。 糖尿病等疾病。尽管有证据表明双TCR细胞的重要性， 这是由于不能明确地鉴定、分离和功能性研究表达双重TCR的T细胞。解决 为此，我们开发了新的方法，包括小鼠和人类细胞的单细胞TCR测序， TCRα荧光报告基因的转基因小鼠。我们希望这些工具能够帮助我们解决 假设，并产生新的见解，基本TCR生物学，以确定潜在的途径，以改善 临床移植