Exploring the mechanisms of T cell intrinsic TLR2 signaling on Treg function

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DESCRIPTION (provided by applicant): This proposal outlines a two-year transitional grant for June L. Round, Ph.D. This grant would be activated once Dr. Round begins an assistant professor position at a research institution and would be used to fund the initial years of her work. Dr. Round is currently a postdoctoral scholar at the California Institute of Technology in the laboratory of Dr. Sarkis K. Mazmanian. Dr. Round's research utilizes the commensal organism, Bacteroides fragilis, as a model bacterial organism to study commensal-host relationships. Her preliminary work has found that a molecule, polysaccharide A (PSA), made by this bacteria mediates protection from the inflammation associated with an animal model of inflammatory bowel disease. She has further demonstrated that this molecule induces a population of T cells, known as T regulatory cells, that are known to actively suppress host inflammatory pathways. She has also found that PSA is able to accomplish this through direct signaling of toll like receptor 2 (TLR2) on a T cell. As TLR signaling was, until recently, thought to be restricted to cells of the innate immune system, this proposal sets forth experiments to understand the signaling pathways that are induced downstream of TLR2 engagement by PSA within Tregs. Additionally, these experiments will utilize in vivo models to understand the contribution of TLR2 on a T cell to PSA mediated anti-inflammatory activity. Finally, she will utilize TLR2 ligands in a step-wise fashion to determine whether these can be used to enhance Treg activity and suppress intestinal disease. As Tregs are known to be protective in multiple allergy and autoimmune models of disease, understanding how Tregs are regulated and how we can manipulate their activity will provide novel cellular therapies. The proposed work will uncover a novel layer of how T cells and more specifically Tregs are regulated and represents a substantial step in harnessing Treg activity for health benefits.