The role of T cell intrinsic TLR signaling on host-commensal interactions

描述(申请人提供)：人类是一个巨大的共生细菌联盟的家园，最近被认为是健康的一个重要组成部分。事实上，微生物群落结构的破坏与多种自身免疫和传染病有关。鉴于致病细菌和共生细菌都有相似的分子基序，目前尚不清楚宿主免疫系统如何区分好细菌和坏细菌。我们以前的研究已经发现了一种新的信号通路，由T细胞用来诱导对共生微生物脆弱芽孢杆菌的耐受。我们鉴定这种生物产生一种多糖(称为PSA)，通过直接连接T细胞上的Toll样受体2(TLR)来特异性地诱导耐受反应。因此，PSA代表了一类新的分子的初始成员，这些分子由共生细菌表达并控制宿主免疫。TLRs是一类受体，很大程度上是在天然免疫的背景下进行研究的。直到最近人们才意识到，TLRs也表达在包括T细胞在内的适应性免疫系统的细胞上。我们的数据表明，T细胞固有的TLR信号是调节宿主-共生相互作用的重要途径。这一建议将寻求更好地了解PSA通过TLR2在T细胞上引发的信号通路，并了解T细胞固有的TLR信号如何影响微生物区系的组成、宿主的发育和健康。

DESCRIPTION (provided by applicant): Humans are home to a vast consortium of commensal bacteria that have recently been suggested to be an important component of health. Indeed, disruptions in microbial community structure has been correlated with multiple autoimmune and infectious disease. Given that both pathogenic and commensal bacteria have similar molecular motifs it remains unclear how the host immune system discriminates between good and bad bacteria. Our previous studies have identified a novel signaling pathway employed by T cells to induce tolerance to the commensal microbe, B.fragilis. We identified that this organism produced a polysaccharide (called PSA) that specifically induces tolerant responses by directly ligating toll like receptor 2 (TLR) on a T cell. Thus, PSA represents the incipient member of a novel class of molecules that are expressed by commensal bacteria and control host immunity. TLRs are a class of receptors that have largely been studied in the context of innate immunity. It has only recently been appreciated that TLRs are also expressed on cells of the adaptive immune system including T cells. Our data suggest that T cell intrinsic TLR signaling is an important pathway that regulates host-commensal interactions. This proposal will seek to better understand the signaling pathway that is elicited by PSA through TLR2 on a T cell and understand how T cell intrinsic TLR signaling influences the composition of the microbiota, host development and health.