Regulation of central tolerance and Treg development by recirculating Treg

项目总结 有效的细胞免疫依赖于两个主要系统：(1)产生不同TCR的能力 能够识别来自以前未见过的病原体的抗原的谱系，以及(Ii)能够 区分自身和非自身抗原，防止自身免疫。不适当的平衡 这两个系统导致多种疾病状态，包括无效的肿瘤免疫监测和糟糕的 由于TCR谱系中的空白或自身免疫和脱靶而导致的病原体清除 感染过程中的免疫病理学。自身免疫可以通过删除自身反应性TCR或转移 它们进入胸腺中的Treg血统。然而，鉴于TCR的高度交叉反应，这 过程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 传统TCR曲目的多样性，从而削弱了对病原体的免疫力。因此，一个关键的生物 问题是胸腺的选择是如何平衡保护和自身免疫的，同时提供 对病原体的有效免疫力。我们假设有一组独特的胸腺循环 Treg细胞(RT-Treg)充当变阻器，以降低外周Treg细胞选择的严谨性 建立了耐受性，从而允许更多样化和病原体反应性的常规 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异质性和 RT-Treg累积的功能后果。目的2：确定RT-Treg细胞影响的机制 免疫谱系和mTEC编号。拟议的实验将阐明RT-Treg在 管理中枢耐受的严格性，既促进效应细胞多样性，又确保维持 特雷格细胞的自我耐受性。

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.