Dual TCR Expression Effects on Alloreactivity and Transplantation

项目摘要/摘要 在正常生理学中，人类T细胞的谱系包括10%的亚群，表达两个，而不是 而不是单一的T细胞受体(TCR)。尽管克隆水平上的双重特异性具有明显的含义，但 这种双重TCR亚群的功能在很大程度上仍不清楚。我们最近提出了新的范式 并提供了证据表明自然产生的双重TCR表达在胸腺生成中是重要的 而且，双TCR细胞具有非凡的识别驱动同种异体反应和自身反应的配体的能力。这 反应性与疾病有关，正如我们在小鼠模型和人类患者中证明的那样，双重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TCR T细胞与自身免疫联系起来 糖尿病等疾病。尽管有证据表明双重TCR细胞的重要性，但对它们的研究还不够充分 由于不能明确地识别、分离和功能研究表达双TCR的T细胞。致信地址 为此，我们开发了新的方法，包括对小鼠和人类细胞进行单细胞TCR测序，以及 TcRα荧光报告基因转基因小鼠。我们希望这些工具将使我们能够解决我们的 假设并对基础TCR生物学产生新的见解，以确定改进的潜在途径 临床移植。

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.