Mechanisms of Immune Regulation in Mycobacterium Tuberculosis Infection

描述（由申请人提供）：结核分枝杆菌感染了全世界大约20亿人，并且可以在宿主的一生中持续存在。免疫控制丧失和进展为活动性肺结核（TB）疾病发生在一小部分感染者中，然而导致这种免疫失败的确切机制尚不清楚。在慢性感染的人类和动物模型中，持续的抗原刺激导致抗原特异性T细胞功能障碍，其特征是细胞因子产生、增殖能力和细胞溶解活性的逐渐丧失。之前在慢性病毒感染的背景下已经描述过T细胞的这种功能性“衰竭”，并且与抗原驱动的抑制受体的上调有关，抑制受体负性地调节抗原特异性T细胞。在活化T细胞上表达的负调节受体包括B7家族成员：程序性死亡1 （PD-1）、细胞毒性T淋巴细胞相关抗原4 （CTLA-4）、B和T淋巴细胞衰减剂（BTLA），以及免疫球蛋白超家族成员：CD160和T细胞免疫球蛋白结构域和粘蛋白结构域3 （TIM-3）。慢性分枝杆菌抗原刺激与负调节活化结核分枝杆菌特异性T细胞的受体表达之间的关系尚未得到解决。这一提议的基本假设是负调节受体的表达与分枝杆菌抗原水平有关，负调节受体的上调与肺结核患者保护性结核分枝杆菌特异性T细胞反应的失调有关。以下具体目标将被解决：(1)表征阴性调节受体在潜伏性和活动性肺结核患者肺细胞上的表达；(2)分析潜伏性和活动性肺结核患者治疗前后外周血负调节受体的特征；(3)确定阻断负调控通路对结核分枝杆菌特异性T细胞功能的影响。这些研究将集中在南非开普敦具有不同分枝杆菌抗原水平的个体，包括无症状潜伏性结核感染（LTBI）、抗酸杆菌（AFB）痰涂片阴性/培养阳性肺结核和AFB痰涂片阳性肺结核。阐明导致活动性结核病患者免疫功能衰竭的机制对于更好地了解结核分枝杆菌的免疫发病机制至关重要，并将为免疫治疗干预和新型结核病疫苗的合理设计提供新的研究途径。公共卫生相关性：在大多数感染结核分枝杆菌的个体中，免疫反应成功地将细菌控制在潜伏状态，而宿主仍然无症状。研究潜伏性和活动性结核病患者中调节结核分枝杆菌特异性T细胞反应的细胞免疫反应机制，对于更好地理解为什么某些感染者进展为活动性结核病的免疫反应失败至关重要；这些研究将为免疫治疗干预和设计更有效的结核病疫苗开辟新的研究途径。

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis infects approximately 2 billion people worldwide and can persist for the lifetime of the host. Loss of immune control and progression to active tuberculosis (TB) disease occurs in a subset of infected individuals, however the precise mechanisms leading to this immunological failure are not known. Persistent antigen stimulation in human and animal models of chronic infections leads to antigen-specific T cell dysfunction, characterized by progressive loss of cytokine production, proliferative capacity, and cytolytic activity. This functional 'exhaustion' of T cells has been previously described in the context of chronic viral infections, and has been associated with antigen-driven upregulation of inhibitory receptors that negatively regulate antigen-specific T cells. Negative regulatory receptors expressed on activated T cells include members of the B7 family: programmed death 1 (PD-1), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and B and T lymphocyte attenuator (BTLA), as well as members of the immunoglobulin superfamily: CD160 and T cell immunoglobulin domain and mucin domain 3 (TIM-3). The relationship between chronic mycobacterial antigen stimulation and expression of receptors that negatively regulate activated M. tuberculosis-specific T cells has not been addressed. The underlying hypothesis of this proposal is that expression of negative regulatory receptors is related to mycobacterial antigen levels, and that upregulation of negative regulatory receptors is associated with dysregulation of protective M. tuberculosis- specific T cell responses in persons with pulmonary TB disease. The following specific aims will be addressed: (1) Characterize expression of negative regulatory receptors on cells from the lungs of individuals with latent and active pulmonary TB; (2) Characterize negative regulatory receptors in peripheral blood of individuals with latent and active pulmonary TB, before and after initiation of treatment; (3) Determine the effect of blockade of negative regulatory pathways on M. tuberculosis-specific T cell function. These studies will focus on individuals in Cape Town, South Africa with different mycobacterial antigen levels, including asymptomatic latent TB infection (LTBI), acid-fast bacilli (AFB) sputum smear- negative/culture-positive pulmonary TB, and AFB sputum smear-positive pulmonary TB. Elucidating mechanisms contributing to immunological failure in persons who develop active TB disease is essential for a better understanding of M. tuberculosis immunopathogenesis, and will facilitate new avenues of research on immunotherapeutic interventions and the rational design of novel TB vaccines. PUBLIC HEALTH RELEVANCE: In the majority of individuals infected with Mycobacterium tuberculosis, the immune response successfully contains the bacteria in a latent state and the host remains asymptomatic. Investigation of mechanisms of the cellular immune response that regulate M. tuberculosis- specific T cell responses in persons with latent and active disease is essential for a better understanding of why the immune response fails in some infected individuals who progress to develop active tuberculosis disease; such studies will open up new avenues of research on immunotherapeutic interventions and the design of more effective tuberculosis vaccines.