T cell compartmentalization and antiviral response

 描述(申请人提供)：T细胞受体(TCR)在主要组织相容性(MHC)分子的背景下识别抗原，这对决定T细胞的命运至关重要 在胸腺发育以及外周激活、分化和记忆发育过程中。作为一个机械传感器，TcR复合体解释多肽-MHC中的信息，并将其从TcRαβ链上的配体结合界面传递到相关的CD3亚单位，转化为以结合/解除结合的形式的激酶/磷酸酶分子及其酶反应的生化信号。在急性解体感染期间，如小鼠的LCMV ARM，幼稚的CD8+T细胞将在感染的第一周内增殖和扩张。这种扩张是抗原特异性的，并依赖于所有共刺激和炎性细胞因子的帮助。如果成功并且病毒被清除，这些细胞中的大多数将在通常持续感染后8-30天的收缩阶段通过凋亡而死亡。然后，这些效应细胞中的一小部分将分化为记忆T细胞，在那里它们可以准备好对召回抗原做出比最初反应更快、更有活力的反应。由于组织驻留的免疫细胞在表型和功能上与血液中循环的细胞不同，因此区分参与局部免疫反应的细胞和在血管系统中循环的细胞是非常有意义的。在本研究中，我们假设抗病毒CD8+T细胞的解剖区隔影响免疫收缩阶段T细胞的TCR-pMHC相互作用和功能分化。这一假设是基于我们最近对有效的2D TCR亲和力的分析，通过高灵敏的二维(2D)方法进行了原位测量。抗病毒CD8+T细胞应答在感染后7-8天达到高峰，随后病毒滴度在第8天消失。令人惊讶的是，在抗病毒免疫应答停止后第9天和第11天，基因完全相同的P14 TCR对脾红髓T细胞的2D TCR亲和力比WP T细胞高约5倍。这些数据表明，差异定位的抗病毒CD8+T细胞从不同的微环境接收不同的信号，从而潜在地影响它们的功能和分化。在这项建议中，我们旨在了解抗病毒CD8+T细胞的解剖定位调节TCR-pMHC相互作用，并潜在地影响抗原特异性T细胞的命运。免疫细胞持续循环，在体内巡逻，寻找入侵的病原体。在感染时，许多免疫细胞在感染部位局部积聚，以更有效地清除病原体，防止感染的传播。这些免疫细胞的特定位置，无论它们是驻留在白髓还是红髓，可能对它们对病原体的反应有多强烈，优先扩张、死亡或成为准备对召回抗原做出比最初反应更快和更有活力的长期记忆细胞具有重要意义。这些定位不同的免疫细胞可能从不同的微环境接收不同的信号，从而潜在地影响它们的功能和分化。

 DESCRIPTION (provided by applicant): The T cell receptor (TCR) recognizes antigen in the context of a major histocompatibility (MHC) molecule, which is critical for determining T cell fate during thymic development as well as peripheral activation, differentiation and memory development. As a mechanosensor, the TCR complex interprets the information embedded in the peptide-MHC and transduces it from the ligand-binding interface across the TCR αβ chains to the associated CD3 subunits into biochemical signals in the form of binding/unbinding of kinase/ phosphatase molecules and their enzymatic reactions. During an acute resolving infection such as LCMV Arm in mice, naïve CD8+ T cells will proliferate and expand during the first week of infection. This expansion is antigen-specific and dependent on help from panoply of co-stimulatory and inflammatory cytokines. If successful and the virus is cleared, the majority of these cells will die by apoptosis during the contraction phase that lasts typically between 8-30 days post infection. A small portion of these effector cells will then differentiate to memory T cells where they can be poised to respond to a recall antigen quicker and with more vigor than during the primary response. Since tissue-resident immune cells are known to be phenotypically and functionally different from cells circulating in the blood, discrimination of cells that particpate in local immune responses and those that are circulating in the vasculature is of great interest. In this study, we hypothesize that the anatomic compartmentalization of anti-viral CD8+ T cells affect TCR-pMHC interaction and functional differentiation of T cells during the immune contraction phase. This hypothesis is based on our recent analysis of effective 2D TCR affinity, measured in situ by highly sensitive two-dimensional (2D) methods. Anti-viral CD8+ T cell responses reach a peak between 7-8 days post infection with subsequent elimination of viral titers by day 8. Surprisingly, the 2D TCR affinity of genetically identical P14 TCR on T cells in the splenic red pulp was increased ~5 fold as compared to that of the WP T cells on days 9 and 11 after the cessation of anti-viral immune responses. These data suggest that differentially localized anti-viral CD8+ T cells receive disparate signals from distinct microenvironments, thus potentially affecting their function and differentiation. In this proposal, we aim to understand ho anatomic localization of anti-viral CD8+ T cells regulates TCR-pMHC interaction and potentially influence the fate of antigen-specific T cells. Immune cells continuously circulate to patrol the body searching for invading pathogens. Upon infection, many immune cells are locally accumulated into the site of infection to more efficiently clear the pathogen and prevent the spread of infection. The specific location of these immune cells, whether they are resident in the white pulp or red pulp may have important implication for how strongly they react to the pathogen, preferentially expand, die or become long lasting memory cells poised to respond to a recall antigen quicker and with more vigor than during the primary response. These differentially localized immune cells may receive disparate signals from distinct microenvironments, thus potentially affecting their function and differentiation.