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留反应性的外周T细胞受体谱系 对抗我们的自身抗原。已经出现了几种机制来管理这种自我反应并防止公开 自身免疫，包括T细胞无能和缺失，以及调节性T细胞的活动。故障： 这种耐受机制被认为是许多自身免疫性疾病的基础。 在研究小鼠的初始CD8+T细胞库时，我们最近观察到一小部分初始T细胞是- 在动态平衡条件下-在依赖MHC-I与迁徙的相互作用期间暴露于活性的转化生长因子-β 淋巴结内的树突状细胞。这种转化生长因子-b的暴露是初始CD8+T细胞高效形成的先决条件 上皮驻留记忆T细胞(ETRM)应对免疫挑战，如皮肤接种病毒 病原体。当这种预适应过程被破坏时，例如在没有淋巴结的情况下，通过防止 树突状细胞向淋巴结迁移，或通过删除转化生长因子-b激活的树突状细胞中的AV-整合素，形成 皮肤中ETRM的含量大大减少，导致抗病毒保护减弱。 在这个项目的初步研究中，我们发现动态平衡的转化生长因子-b条件作用发生。 优先于弱自身反应的CD8+T细胞，而较强的自身反应细胞不受条件作用。 从机制上讲，依赖于TCR的ERK活性似乎通过一种抑制作用来限制转化生长因子-b信号。 Smad2和Smad3转录因子中连接区的磷酸化，阻止其核 易位及其对基因转录的影响。 基于这些观察，我们假设动态平衡的转化生长因子-b信号调节初始CD8+T细胞 对于长寿命上皮细胞的形成，驻留记忆细胞被限制在构成最低风险的细胞 导致自身免疫。在这个项目中，我们将通过比较幼稚的TCR自我反应性来检验这一假设 CD8+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学变化 条件幼稚T细胞的特征及其与ETRM过程中激活的基因程序的关系 差异化。如果我们的假设得到证实，我们的研究可能会揭示一种新的机制，通过这种机制自动- 管理外围TCR曲目中的反应性。这一机制的崩溃可能是 出现在皮肤等屏障组织中的自身免疫性疾病。

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.