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

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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.