The role of regulatory T cells in M. tuberculosis infection

描述（由申请人提供）：越来越多的证据表明Tregs在预防自身免疫、抑制移植排斥、抑制肿瘤和微生物病原体的免疫反应中起着关键作用。然而，关于Tregs在结核分枝杆菌感染中的作用的信息有限，结核分枝杆菌是一种在世界范围内引起巨大发病率和死亡率的病原体。最近，我们发现，在健康的结核菌素反应器中，t细胞通过单核细胞增强前列腺素E2 （PGE2）的产生，而PGE2有利于Tregs的扩增。此外，NK细胞通过直接裂解Treg抑制Treg扩增以应对结核分枝杆菌。本研究将通过以下目的来描述巨噬细胞和NK细胞在健康的结核菌素反应器中影响Tregs扩增的机制。1)确定结核分枝杆菌感染单核细胞扩增Tregs的细胞机制。我们将确定可溶性T细胞因子和介导T细胞的因子：单核细胞间接触，增加PGE2的产生，扩大Tregs，以应对结核分枝杆菌感染。有利于Treg扩增的单核细胞亚群也将被确定。2)确定NK细胞抑制Tregs扩增的机制，重点研究NK细胞裂解Tregs的机制。这些研究将提供一个更好的理解机制，介导Treg扩增对细胞内细菌感染的反应。获得的信息将有助于我们设计更有效的抗结核疫苗，并为开发基于抑制Treg发展的免疫治疗策略奠定基础。结核病是传染性病原体导致死亡的主要原因，每年在全世界夺去190万人的生命。大多数感染结核分枝杆菌的人保持健康并具有保护性免疫，但10%的感染者在感染或多年后再激活结核病后不久发展为原发性结核病。了解调节针对结核分枝杆菌的保护性免疫反应的因素对于开发有效的疫苗至关重要。最近，人们的注意力集中在调节性CD4+ t细胞（Tregs）上，它们可以抑制对不同感染因子的免疫反应。然而，关于这些生物在人类感染中扩大Tregs的能力的信息有限。在本提案中，我们将确定参与Treg扩增的细胞机制，这些信息将为基于Treg的治疗的发展奠定基础，以减少过度活跃的免疫系统造成的组织损伤。这些研究还将为某些个体中可能导致结核病复发的机制提供线索。我们还将确定自然杀伤细胞（一种特殊类型的血细胞）破坏Treg并因此抑制Treg扩增的机制，这是一种以前从未探索过的可能性。这些研究将提供对结核分枝杆菌和其他细菌的免疫反应的基本信息。它们将促进制定加强免疫反应的战略，从而预防和治疗结核病和其他感染，特别是在免疫缺陷的免疫功能低下者中。

DESCRIPTION (provided by applicant): 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 productionand 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.Tuberculosis is a leading cause of death from infectious agents, claiming 1.9 million lives worldwide annually. Most persons who are infected with Mycobacterium tuberculosis remain healthy and have protective immunity, but 10% of infected individuals develop primary tuberculosis soon after infection or reactivation tuberculosis many years later. Understanding the factors that regulate protective immune responses against M. tuberculosis is essential for development of an effective vaccine. Recently, attention has been focused on regulatory CD4+ T-cells (Tregs), which are known to dampen the immune response to different infectious agents. However, limited information is available on the capacity of these organisms to expand Tregs in human infection. In this proposal, we will determine the cellular mechanisms involved in Treg expansion, information which will lay the foundation for development of Treg-based therapy to reduce tissue damage from an overactive immune system. These studies will also yield clues to the mechanisms that may underlie reactivation of tuberculosis in some individuals. We will also determine the mechanism by which natural killer cells, a special type of blood cell, destroy Tregs and therefore inhibit Treg expansion, a possibility that has not been previously explored. These studies will provide fundamental information on the immune response to M.tuberculosis and other bacteria. They will facilitate development of strategies to strengthen the immune response, thereby preventing and treating tuberculosis and other infections, particularly in immunocompromised persons with defective immunity.