Defining tolerance mechanisms regulating self-specific T cells

摘要 适应性免疫系统依靠严格的免疫耐受机制来确保自身组织 免受自身免疫攻击。这种免疫调节的失败和成功具有重要意义 对自身免疫性疾病预防和抗肿瘤免疫治疗效果的影响。因此， 人们对确定调节自身特异性T细胞反应的普遍机制非常感兴趣 抗原，希望这些过程可以被操纵，为临床带来好处。虽然许多自身反应性T细胞 细胞被认为是通过克隆删除从传统的T(Tconv)细胞库中清除出来的，实质上 有证据表明，这一过程并不完美。在这方面，人们对自我反应的本质知之甚少 T细胞存在于内源性谱系中。例如，目前还不清楚大多数自身特异的T细胞是否 对广泛性抗原或组织限制性抗原的反应，以及这些细胞是否稳定受到限制 通过细胞内在机制，如功能失活或显性机制，如Treg- 居间压制。此外，在癌症的背景下，很难定义自身特异性T细胞 细胞有助于肿瘤浸润性淋巴细胞(TIL)的谱系，或者大多数TIL是否是非特异性的 T细胞通过TCR非依赖性炎症信号被募集到肿瘤中。在这项提案中，我们将 通过追求以下具体目标来解决这些悬而未决的问题。在目标1中，我们将确定CD4+T细胞 在Treg细胞消融后，内源性T细胞库中渗透到前列腺的细胞克隆，以及 确定这些细胞所识别的自身抗原的性质。在目标2中，我们将定义容差 调控这些Tconv细胞克隆的机制。在目标3中，我们将确定这些自我- 癌基因驱动的小鼠前列腺癌中肿瘤浸润的特异性T细胞克隆型。我们将实现 这些目的是通过检验中心假设，即内源性T细胞谱系包含一池自身 特异的Tconv细胞对前列腺特异性抗原产生反应，并抑制前列腺和前列腺癌 这些细胞对肿瘤的侵袭依赖于Treg介导的抑制。预计这项工作将 在这项提案中概述的将证明胸腺和外周细胞的缺失对许多自我- 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 组织渗入。此外，我们预计Treg耗尽后，Tconv细胞会渗入前列腺。 会表现出对器官特异的前列腺抗原的反应性，而不是广泛存在的自身抗原。最后，它是 预计自身特异的Tconv细胞将占前列腺癌浸润性T细胞的很大比例 细胞谱系。总而言之，我们的工作有望为我们对机制的理解提供新的见解 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.