T Cell Memory in Organ Transplantation

摘要 记忆T细胞在同种异体移植排斥反应中起关键作用。他们代表了相当大的比例 同种异体反应性T细胞在驱动效应器机制方面优于初始T细胞 急性和慢性排斥反应。 移植免疫记忆的研究主要集中在循环效应器方面 (TM)和中枢(Tcm)记忆T细胞。最近的研究已经确定了大量的非 在非淋巴组织中提供局部免疫的循环驻留记忆T细胞(TRM) 并且在表型、转录和功能上都不同于透射电子显微镜和中医。TRM- 已经在人的小肠和肺移植中发现了表型细胞，但它们的生物学 在移植中的作用和作用还知之甚少。 在过去的资助期间，我们建立了小鼠肾移植模型，在该模型中， 同种异体移植经历缓慢的慢性排斥反应，以及单克隆性和多克隆性T细胞渗入 随着时间的推移，贪污可以被追踪和审问。使用这个模型，我们可以证明TRM (由它们的表型、转录特征、非循环行为和功能定义)形式 移植并导致排斥反应。这就引出了TRM在当地维持的中心论点 并在当地维持排斥反应。在本应用程序中，我们建议调查TRM是如何维护的 在异体移植物中。在目标1中，我们将研究抗原、树突状细胞和细胞因子的作用。 IL-15。在目标2中，我们将研究特定转录和转录后的作用 单细胞转录分析确定的促进细胞增殖的调节因子(Ebp1) 和生存。在这两个目标中，我们将研究中断TRM维护对慢性 拒绝。回答这些问题有望产生新的生物学和治疗见解。 适用于器官移植排斥和可能的其他疾病，如移植物抗宿主病和 自身免疫力。

Abstract Memory T cells play a key role in allograft rejection. They represent a sizeable proportion of the alloreactive T cell repertoire and are superior to naive T cells in driving the effector mechanisms of acute and chronic rejection. Much of the research on immune memory in transplantation has focused on circulating effector (TEM) and central (TCM) memory T cells. Recent studies have identified large populations of non- circulating, resident memory T cells (TRM) that provide local immunity in non-lymphoid tissues and are phenotypically, transcriptionally, and functionally distinct from TEM and TCM. TRM- phenotype cells have been identified in human small bowel and lung allografts but their biology and function in transplantation are poorly understood. During the past funding period, we established a mouse kidney transplantation model in which allografts undergo slow, chronic rejection, and monoclonal and polyclonal T cells that infiltrate the graft can be tracked and interrogated over time. Using this model, we could show that TRM (defined by their phenotype, transcriptional profile, non-circulatory behavior, and function) form in the graft and contribute to rejection. This led to the central thesis that TRM are maintained locally and sustain rejection locally. In this application we propose to investigate how TRM are maintained in the allograft. In Aim 1, we will investigate the roles of antigen, dendritic cells, and the cytokine IL-15. In Aim 2, we will investigate the role of a specific transcriptional and post-transcriptional regulator (Ebp1), identified by single cell transcriptional analysis, that enhances cell proliferation and survival. In both aims we will study the effects of interrupting TRM maintenance on chronic rejection. Answering these questions promises to yield novel biological and therapeutic insights applicable to organ transplant rejection and possibly other diseases such as GVHD and autoimmunity.