Defining tolerance mechanisms regulating self-specific T cells

摘要 适应性免疫系统依赖于严格的免疫耐受机制，以确保自身组织被 免受自身免疫攻击这种免疫调节的成功和失败具有重要意义。 对预防自身免疫性疾病和抗肿瘤免疫疗法功效的影响。因此，在本发明中， 人们对确定调节T细胞对自身免疫应答特异性的主要机制很感兴趣， 抗原，希望这些过程可以被操纵用于临床益处。虽然许多自身反应性T 细胞被认为通过克隆缺失从常规T（Tconv）细胞库中清除， 有证据表明，这一进程并不完善。在这方面，对自反应的性质知之甚少。 T细胞存在于内源性库中。例如，目前尚不清楚大多数自身特异性T细胞是否是 对广泛分布的抗原或组织限制性抗原有反应，以及这些细胞是否在稳定的 通过细胞内在机制如功能失活或显性机制如Treg- 介导的抑制。此外，在癌症的背景下，很难确定自身特异性T 细胞对肿瘤浸润淋巴细胞（TIL）的库有贡献，或者大多数TIL是否是非特异性的 通过TCR非依赖性炎症信号募集到肿瘤的T细胞。在本提案中，我们将 通过实现以下具体目标来解决这些悬而未决的问题。在目标1中，我们将识别CD 4 + T 在Treg细胞消融后浸润前列腺的内源性T细胞库中的细胞克隆，和 确定这些细胞识别的自身抗原的性质。在目标2中，我们将定义公差 调节这些Tconv细胞克隆的机制。在目标3中，我们将确定这些自我的贡献， 特异性T细胞克隆型对癌基因驱动的小鼠前列腺肿瘤中肿瘤浸润的影响。我们将实现 这些目标是通过测试中心假设，即内源性T细胞库包含一个自我调节池， 特异性Tconv细胞对前列腺特异性抗原有反应，并且前列腺和前列腺上皮细胞的抑制可能与前列腺特异性抗原有关。 这些细胞的肿瘤浸润依赖于Treg介导的抑制。预计这项工作 在这个提议中概述的将证明，胸腺和外周缺失几乎不会阻碍许多自我， 特异性Tconv克隆型，Treg介导的抑制在限制自身免疫中起关键作用， 组织浸润此外，我们预期Treg耗竭后浸润前列腺的Tconv细胞 将对器官特异性前列腺抗原而不是广泛的自身抗原表现出反应性。最后是 预期自身特异性Tconv细胞将构成前列腺肿瘤浸润性T细胞的相当大的比例。 细胞库总之，我们的工作有望在我们对机制的理解中产生新的见解 潜在的免疫耐受和抗肿瘤免疫。

ABSTRACT The adaptive immune system relies on stringent immune tolerance mechanisms to ensure that self-tissues are protected from autoimmune attack. The failure and success of such immune regulation have important implications in the prevention of autoimmune diseases and the efficacy of anti-tumor immune therapies. Thus, there is great interest in defining the prevailing mechanisms that regulate T cell responses specific for self- antigens, in the hopes that these processes can be manipulated for clinical benefit. While many autoreactive T cells are thought to be purged from the conventional T (Tconv) cell repertoire by clonal deletion, substantial evidence suggests that this process is imperfect. In this regard, little is known about the nature of self-reactive T cells present in the endogenous repertoire. For example, it is unclear whether most self-specific T cells are reactive to widespread antigens or tissue-restricted antigens, and whether these cells are restricted at steady state by cell-intrinsic mechanisms such as functional inactivation or dominant mechanisms such as Treg- mediated suppression. Moreover, in the context of cancer, it has been difficult to define whether self-specific T cells contribute to the repertoire of tumor-infiltrating lymphocytes (TILs), or whether most TILs are non-specific T cells that are recruited to the tumor by TCR-independent inflammatory signals. In this proposal, we will address these unanswered questions by pursuing the following specific aims. In Aim 1, we will identify CD4+ T cell clones in the endogenous T cell repertoire that infiltrate the prostate following Treg cell ablation, and determine the nature of the self-antigens recognized by these cells. In Aim 2, we will define the tolerance mechanisms regulating these Tconv cell clones. In Aim 3, we will determine the contribution of these self- specific T cell clonotypes to the tumor infiltrate in oncogene-driven mouse prostate tumors. We will achieve these aims by testing the central hypothesis that the endogenous T cell repertoire contains a pool of self- specific Tconv cells reactive to prostate-specific antigens, and that the suppression of prostate and prostate tumor infiltration by these cells is dependent on Treg-mediated suppression. It is expected that the work outlined in this proposal will demonstrate that thymic and peripheral deletion does little to impede many self- specific Tconv clonotypes, and that Treg-mediated suppression plays a pivotal role in restricting autoimmune tissue infiltration. In addition, we anticipate that the Tconv cells infiltrating the prostate following Treg depletion will exhibit reactivity to organ-specific prostatic antigens rather than widespread self-antigens. Finally, it is expected that self-specific Tconv cells will constitute a substantial proportion of the prostate tumor-infiltrating T cell repertoire. In all, our work is expected to yield new insights in our understanding of the mechanisms underlying immune tolerance and anti-tumor immunity.