Regulation of central tolerance and Treg development by recirculating Treg

项目摘要 有效的基于细胞的免疫取决于两个主要系统：（i）产生多样化TCR的能力， 能够识别来自以前未遇到的病原体的抗原的库，和（ii）能够 区分自身抗原和非自身抗原，防止自身免疫。之间不平衡 这两种系统导致多种疾病状态，包括无效的肿瘤免疫监视和不良的免疫反应。 由于TCR库中的缺口或自身免疫和脱靶的发作而导致的病原体清除 感染期间的免疫病理学。自身免疫可以通过删除自身反应性TCR或转移 进入胸腺中的Treg谱系。然而，考虑到TCR的高度交叉反应性， 该方法不能真正有效地去除所有自反应TCR，因为这将去除大部分潜在的TCR。 常规TCR库的多样性，从而削弱对病原体的免疫力。因此，一个关键的生物学 问题是胸腺的选择功能如何平衡对自身免疫的保护，同时提供 对病原体有有效的免疫力。我们假设一个独特的胸腺再循环群体 Treg细胞（RT-Treg）充当变阻器以降低选择的严格性，一旦外周Treg细胞被激活， 建立耐受性，从而允许更多样化和病原体反应性的常规治疗。 免疫系统这将在两个具体目标中进行检查：目标1：定义RT-Treg异质性， RT-Treg积累的功能后果。目的2：确定RT-Treg细胞影响细胞增殖的机制。 免疫谱系和mTEC数量。所提出的实验将阐明RT-Treg在以下方面发挥的作用： 控制中枢耐受的严格性，既促进效应细胞多样性，又确保维持 自身耐受性的机制。

PROJECT SUMMARY Effective cell-based immunity depends on two major systems: (i) the ability to generate a diverse TCR repertoire capable of recognizing antigens from previously unencountered pathogens, and (ii) the ability to discriminate between self- and non-self-antigens and prevent autoimmunity. Inappropriate balance between these two systems causes a variety of disease states including ineffective tumor immune surveillance and poor pathogen clearance due to gaps in the TCR repertoire, or the onset of autoimmunity and off target immunopathology during infection. Autoimmunity can be curtailed by deleting autoreactive TCRs or diverting them into the Treg lineage in the thymus. However, given the high degree of cross-reactivity of TCRs this process cannot be truly efficient at removing all self-reactive TCRs as this would remove much of the potential diversity of the conventional TCR repertoire, thereby impairing immunity to pathogens. Thus, a key biological question is how thymic selection functions to balance protection against autoimmunity while providing effective immunity against pathogens. We hypothesize that a unique population of thymic recirculating Treg cells (RT-Treg) act as a rheostat to decrease the stringency of selection once peripheral Treg cell tolerance is established, thereby allowing for a more diverse and pathogen-reactive conventional immune system. This will be examined in two specific aims: Aim 1: Define RT-Treg heterogeneity and functional consequences of RT-Treg accumulation. Aim 2: Identify the mechanisms by which RT-Treg cells affect immune repertoires and mTEC numbers. The proposed experiments will elucidate the role that RT-Treg play in governing the stringency of central tolerance, both promoting effector cell diversity and ensuring maintenance of self-tolerance by Treg cells.