The role of regulatory T cells in M. tuberculosis infection

越来越多的证据表明，Treg在预防自身免疫方面发挥着关键作用， 抑制移植排斥反应，抑制对肿瘤的免疫反应，并 微生物病原体。然而，关于Tregs在疾病中的作用的信息有限 由结核分枝杆菌引起的感染，这种病原体导致巨大的发病率和 世界范围内的死亡率。最近，我们发现，在健康的结核菌素反应堆中，T细胞 促进单核细胞产生前列腺素E2(PGE2)，PGE2有利于 Tregs的扩展。此外，NK细胞还能抑制M。 通过直接裂解Tregs而得的结核病。这项提议将通过以下方式描述这些机制 巨噬细胞和NK细胞对健康结核菌素Tregs扩增的影响 反应堆通过以下目标。1)确定通过哪些细胞机制 结核分枝杆菌感染的单核细胞可扩增Tregs。我们将鉴定可溶性T细胞 调节T细胞的因素和因素：单核细胞与细胞间接触增加 PGE2的产生和扩展Tregs以应对结核分枝杆菌感染。这个 支持Treg扩增的单核细胞亚群也将被确定。2)确定 NK细胞抑制Tregs扩张的机制，重点是 NK细胞裂解Tregs的机制。这些研究将提供一个改进的 对介导Treg扩增的机制的理解 细胞内细菌感染。所获得的信息将帮助我们设计更多 有效的抗结核疫苗，并为开发 基于抑制Treg发展的免疫治疗策略。

Mounting evidence indicates that Tregs play a critical role in preventing autoimmunity, inhibiting transplant graft rejection, suppressing immune response to tumors and to microbial pathogens. However limited information is available about the role of Tregs in infection due to M. tuberculosis, a pathogen that causes tremendous morbidity and mortality world-wide. Recently, we found that, in healthy tuberculin reactors, T-cells enhance production of prostaglandin E2 (PGE2) by monocytes, and PGE2 favors expansion of Tregs. In addition, NK cells inhibit Treg expansion in response to M. tuberculosis by direct lysis of Tregs. This proposal will characterize the mechanisms by which macrophages and NK cells affect expansion of Tregs in healthy tuberculin reactors through the following aims. 1) Determine the cellular mechanisms by which M. tuberculosis-infected monocytes expand Tregs. We will identify the soluble T cell factors and the factors mediating T-cell:monocyte cell-to-cell contact that increase PGE2 production and expand Tregs in response to M. tuberculosis infection. The monocyte subpopulation that favors Treg expansion will also be identified. 2) Determine the mechanisms by which NK cells inhibit expansion of Tregs, focusing on mechanisms by which NK cells lyse Tregs. These studies will provide an improved understanding of the mechanisms that mediate Treg expansion in the response to intracellular bacterial infection. The information gained will help us to design more effective antituberculosis vaccines, and to lay the groundwork for developing immunotherapeutic strategies based on inhibiting Treg development.