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6月L·朗德博士的两年过渡性补助金。一旦朗德博士开始在研究机构担任助理教授职位，这笔补助金将被激活，并将用于资助她最初几年的工作。朗特博士目前是加州理工学院萨基斯·K·马兹马尼亚博士实验室的博士后学者。朗德博士的研究利用共生生物体脆弱类杆菌作为模式细菌生物体来研究共生-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)可以介导对炎症性肠病动物模型相关炎症的保护。她进一步证明，这种分子可以诱导一群T细胞，也就是众所周知的T调节细胞，这种T细胞可以主动抑制宿主炎症途径。她还发现，PSA能够通过直接向T细胞上的Toll样受体2(TLR2)发出信号来实现这一点。由于直到最近，TLR信号还被认为仅限于先天免疫系统的细胞，因此该建议提出了一些实验，以了解TLR2参与的下游信号通路是由Tregs内的PSA诱导的。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，她将循序渐进地利用TLR2配体来确定这些配体是否可以用于增强Treg活性和抑制肠道疾病。众所周知，Tregs在多种过敏和自身免疫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动，将提供新的细胞疗法。这项拟议的工作将揭示T细胞，更具体地说，Treg是如何受到调控的一个新层面，并代表着在利用Treg活性促进健康方面迈出了实质性的一步。

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.