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

描述（由申请人提供）：本提案概述了为June L. Round博士提供的为期两年的过渡资助。该资助将在Round博士在研究机构开始担任助理教授职位后启动，并将用于资助她最初几年的工作。Round博士目前是加州理工学院Sarkis K. Mazmanian博士实验室的博士后学者。Round博士的研究利用共生生物脆弱拟杆菌（Bacteroides fragilis）作为模型细菌生物来研究共生-宿主关系。她的初步工作发现，由这种细菌产生的一种分子，多糖a (PSA)，与炎症性肠病的动物模型有关。她进一步证明，这种分子诱导了一群T细胞，被称为T调节细胞，已知能积极抑制宿主炎症途径。她还发现，PSA能够通过T细胞上toll样受体2 （TLR2）的直接信号传导来实现这一目标。由于TLR信号通路直到最近才被认为局限于先天免疫系统的细胞，因此本研究提出了通过实验来了解Tregs中PSA诱导TLR2参与下游的信号通路。此外，这些实验将利用体内模型来了解T细胞上TLR2对PSA介导的抗炎活性的贡献。最后，她将逐步利用TLR2配体来确定这些配体是否可用于增强Treg活性和抑制肠道疾病。由于Tregs在多种过敏和自身免疫性疾病模型中具有保护作用，了解Tregs是如何调节的以及我们如何操纵它们的活性将提供新的细胞治疗方法。这项提议的工作将揭示T细胞和更具体的Treg是如何被调节的一个新层面，并代表着利用Treg活性促进健康益处的重要一步。

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.