Mechanisms controlling memory CD8 T cell recognition of autoantigen

描述（由申请方提供）：对自身抗原的耐受性维持在多个水平。虽然中枢耐受对于预防自身免疫是必不可少的，但自身反应性T和B细胞仍然存在于外周库中。因此，外周耐受组织特异性和发育调节抗原是必要的，以维持组织的稳态。在某些情况下，由感染产生的交叉反应性记忆细胞可能通过在持续的炎症事件的背景下识别自身抗原而引起自身免疫。我们现在已经设计了一种可诱导的和可逆的系统，其允许在内源性记忆性CD8 T细胞中询问T细胞耐受诱导。我们的数据表明，记忆性CD8 T细胞对自身抗原的反应很差，即使是在树突状细胞（DC）表达的情况下，尽管抗原很容易被幼稚的CD8 T细胞识别。然而，炎症信号的包含部分克服了记忆性CD8 T细胞对自身抗原的无知。因此，在没有炎症的情况下，记忆性CD8 T细胞被禁止发生自身反应性。这些结果导致耐受性通过在稳态条件下不允许记忆性CD8 T细胞识别自身抗原来维持的假设。我们的目标是确定记忆性CD8 T细胞忽略直接DC抗原呈递的机制，并测试组织特异性抗原是否也被忽略。这一目标将通过两个具体目标实现：目标1。确定阻止记忆性CD8 T细胞识别DC表达抗原的解剖学限制。目标2.确定记忆性CD8 T细胞是否会在没有炎症的情况下识别交叉呈递的组织特异性抗原。我们的新系统将提供一个强有力的工具，用于识别可避免或控制自身免疫的机制。

DESCRIPTION (provided by applicant): Tolerance to self-antigens is maintained at multiple levels. While central tolerance is essential to preventing autoimmunity, autoreactive T and B cells nevertheless are present in the peripheral repertoire. Thus, peripheral tolerance to tissue-specific and developmentally regulated antigens is necessary to sustain tissue homeostasis. In some cases, cross-reactive memory cells produced by infection are likely to be responsible for autoimmunity via recognition of self-antigens in the context of ongoing inflammatory events. We have now devised an inducible and reversible system that allows interrogation of T cell tolerance induction in endogenous memory CD8 T cells. Our data show that memory CD8 T cells responded poorly to self-antigen even when expressed by dendritic cells (DC) and despite the fact that the antigen was readily recognized by na�ve CD8 T cells. However, the inclusion of inflammatory signals partially overcame memory CD8 T cell ignorance of self-antigen. Thus, memory CD8 T cells were prohibited from autoreactivity in the absence of inflammation. These results led to the hypothesis that tolerance is maintained by disallowing memory CD8 T cell recognition of self antigen under homeostatic conditions. Our goal is to determine the mechanism by which memory CD8 T cells ignore direct DC antigen presentation and test whether tissue-specific antigens are also ignored. This goal will be achieved through two specific aims: Aim 1. To determine the anatomical constraints prohibiting memory CD8 T cell recognition of DC-expressed antigen. Aim 2. To determine whether memory CD8 T cells will recognize cross-presented tissue-specific antigen in the absence of inflammation. Our new system will provide a powerful tool for identifying the mechanisms by which autoimmunity may be avoided or controlled.