A mechanism to minimize auto-reactivity in the tissue-resident memory T cell pool

项目摘要 胸腺T细胞发育产生具有显著残余反应性的外周T细胞受体库 对抗自身抗原已经出现了几种机制来管理这种自我反应并防止明显的 自身免疫，包括T细胞无反应性和缺失，以及调节性T细胞的活性。失败 这种耐受机制被认为是许多自身免疫性疾病的基础。 在研究小鼠中的幼稚CD 8 + T细胞库时，我们最近观察到一部分幼稚T细胞是- 在稳态条件下-在MHC-I依赖性与迁移性细胞相互作用期间暴露于活性TGF-β 淋巴结中的树突状细胞。这种TGF-b暴露预处理初始CD 8 + T细胞以有效地形成 上皮驻留记忆T细胞（eTRM）在免疫挑战，如针对病毒的皮肤疫苗接种后， 病原体当这种预处理过程被破坏时，例如在没有淋巴结的情况下，通过防止 树突状细胞迁移到淋巴结，或通过缺失树突状细胞中的TGF-β激活α V-整联蛋白， eTRM在皮肤中的含量大大减少，导致抗病毒保护作用减弱。 在这个项目的初步研究中，我们发现，体内平衡的TGF-β调节发生在 优选地在弱自身反应性CD 8 + T细胞中，而更强的自身反应性细胞不受调节。 从机制上讲，TCR依赖性ERK活性似乎通过抑制TGF-β信号传导来限制TGF-β信号传导。 Smad 2和Smad 3转录因子中连接区的磷酸化， 易位和对基因转录的影响。 基于这些观察，我们假设稳态TGF-β信号调节幼稚CD 8 + T细胞 对于长寿命上皮驻留记忆细胞的形成， 引起自身免疫。在这个项目中，我们将测试这一假设，通过比较TCR自身反应性在幼稚 CD 8 + T细胞以及皮肤和其他屏障组织中的eTRM池，并通过检查表观遗传变化 表征条件初始T细胞及其与eTRM期间激活的基因程序的关系 分化如果我们的假设得到证实，我们的研究可能揭示一种新的机制， 控制外周TCR库中的反应性。这一机制的崩溃可能导致 在皮肤等屏障组织中表现出的自身免疫性疾病。

Project Summary Thymic T cell development produces peripheral T cell receptor repertoires with significant residual reactivity against our self-antigens. Several mechanisms have emerged to manage this self-reactivity and prevent overt auto-immunity, including T cell anergy and deletion, as well as the activities of regulatory T cells. Failure of such tolerance mechanisms is thought to underlie many autoimmune disease. In studying the naive CD8+ T cell pool in mice, we have recently observed that a fraction of naive T cells are – under homeostatic conditions – exposed to active TGF-b during MHC-I-dependent interactions with migratory dendritic cells in lymph nodes. This TGF-b exposure pre-conditions naive CD8+ T cells to efficiently form epithelial-resident memory T cells (eTRM) upon immune challenges, such as skin vaccination against viral pathogens. When this pre-conditioning process is disrupted, e.g. in the absence of lymph nodes, by preventing dendritic cell migration to lymph nodes, or by deleting TGF-b-activating aV-integrins in dendritic cells, formation of eTRM in skin is strongly reduced, causing diminished antiviral protection. In preliminary studies for this project we have discovered that homeostatic TGF-b conditioning occurs preferentially in weakly self-reactive CD8+ T cells, while more strongly self-reactive cells are not conditioned. Mechanistically, TCR-dependent ERK activity appears to restrict TGF-b signaling through an inhibitory phosphorylation of the linker region in Smad2 and Smad3 transcription factors that prevents their nuclear translocation and effects on gene transcription. Based on these observations we hypothesize that homeostatic TGF-b signals that condition naive CD8+ T cells for the formation of long-lived epithelial resident memory cells are restricted to cells that pose the lowest risk of causing autoimmunity. In this project we will test this hypothesis by comparing TCR self-reactivity in naive CD8+ T cells as well as the eTRM pools in skin and other barrier tissues, and by examining epigenetic changes that characterize conditioned naive T cells and their relation to gene programs activated during eTRM differentiation. If our hypothesis is confirmed, our studies could reveal a new mechanism by which auto- reactivity in the peripheral TCR repertoire is managed. Breakdown of this mechanism could underlie autoimmune diseases that manifest in barrier tissues such as the skin.