Mechanisms of Immune Regulation in Mycobacterium Tuberculosis Infection

描述（由申请人提供）：结核分枝杆菌感染全球约20亿人，并可持续宿主的一生。免疫控制的丧失和进展为活动性结核病（TB）疾病发生在感染个体的子集中，然而导致这种免疫失败的确切机制尚不清楚。慢性感染的人类和动物模型中的持续抗原刺激导致抗原特异性T细胞功能障碍，其特征在于细胞因子产生、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“耗竭”先前已经在慢性病毒感染的背景下描述，并且已经与负调节抗原特异性T细胞的抑制性受体的抗原驱动的上调相关。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）和B和T淋巴细胞衰减因子（BTLA），以及免疫球蛋白超家族成员：CD 160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分枝杆菌受体表达之间的关系。结核病特异性T细胞尚未得到解决。该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相关，负调节受体的上调与保护性M.肺结核病患者的结核特异性T细胞反应。将解决以下具体目标：（1）表征潜伏性和活动性肺TB个体肺细胞上负调节受体的表达;（2）表征治疗开始前后潜伏性和活动性肺TB个体外周血中负调节受体的表达;（3）确定阻断负调节途径对M.结核特异性T细胞功能。这些研究将重点关注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TB感染（LTBI）、抗酸杆菌（AFB）痰涂片阴性/培养阳性肺TB和AFB痰涂片阳性肺TB。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至关重要。结核病免疫发病机制，并将促进新的途径的研究免疫干预和合理设计的新型结核病疫苗。公共卫生相关性：在大多数感染结核分枝杆菌的个体中，免疫应答成功地将细菌保持在潜伏状态，并且宿主保持无症状。探讨了调节M.在潜伏性和活动性结核病患者中的结核特异性T细胞应答对于更好地理解为什么免疫应答在一些发展为活动性结核病的感染个体中失败是必不可少的; 2这样的研究将为免疫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.