Mechanisms of Immune Regulation in Mycobacterium Tuberculosis Infection

描述(申请人提供)：结核分枝杆菌感染全世界约20亿人，并可持续宿主的一生。免疫控制丧失和发展为活动性结核病(TB)疾病发生在感染的一部分人中，但导致这种免疫失败的确切机制尚不清楚。在慢性感染的人和动物模型中，持续的抗原刺激导致抗原特异性T细胞功能障碍，其特征是细胞因子的产生、增殖能力和细胞溶解活性的进行性丧失。T细胞的这种功能性‘耗尽’以前曾在慢性病毒感染的背景下被描述过，并与抗原驱动的抑制性受体上调有关，后者对抗原特异的T细胞进行负面调节。表达在活化T细胞上的负性调节受体包括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淋巴细胞衰减器(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的结核分枝杆菌特异性T细胞受体的表达之间的关系尚未得到解决。这一建议的基本假设是，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病患者保护性结核分枝杆菌特异性T细胞反应的调节失调有关。具体目标如下：(1)鉴定潜伏期和活动期肺结核患者肺细胞上负性调节受体的表达；(2)检测潜伏期和活动期肺结核患者治疗前后外周血中负性调节受体的表达情况；(3)确定阻断负性调节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有不同分枝杆菌抗原水平的个人，包括无症状潜伏性结核病感染(LTBI)、抗酸杆菌(AFB)痰涂片阴性/培养阳性肺结核以及AFB痰涂片阳性肺结核。阐明导致活动性结核病患者免疫失败的机制对于更好地了解结核分枝杆菌的免疫发病机制是至关重要的，并将促进免疫治疗干预研究的新途径和新型结核病疫苗的合理设计。公共卫生相关性：在大多数感染结核分枝杆菌的人中，免疫反应成功地将细菌控制在潜伏状态，宿主保持无症状。在潜伏期和活动性疾病患者中，研究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在一些进展为活动性结核病的感染者中免疫反应失败是至关重要的；这类研究将为免疫治疗干预和设计更有效的结核病疫苗的研究开辟新的途径。

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.