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

描述（由申请人提供）：人类是大量共生细菌的家园，这些共生细菌最近被认为是健康的重要组成部分。事实上，微生物群落结构的破坏与多种自身免疫性和传染性疾病有关。鉴于致病细菌和共生细菌具有相似的分子基序，宿主免疫系统如何区分好细菌和坏细菌仍不清楚。我们之前的研究已经确定了一种新的信号通路，由T细胞诱导对共生微生物脆弱芽孢杆菌的耐受性。我们发现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）特异性地诱导耐受性反应。因此，PSA代表了一类由共生细菌表达并控制宿主免疫的新分子的早期成员。tlr是一类在先天免疫中被广泛研究的受体。直到最近人们才认识到，tlr也在适应性免疫系统的细胞上表达，包括T细胞。我们的数据表明，T细胞内在的TLR信号是调节宿主-共生相互作用的重要途径。该提案将寻求更好地了解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群的组成、宿主发育和健康。

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.