Mechanisms of recognition by Mycobacterium tuberculosis-reactive thymocytes

描述(由申请人提供)：项目摘要：结核分枝杆菌(Mtb)感染了全世界约三分之一的人口。据估计，每年有800万新病例和200万人死亡，使结核病成为一个重大的健康问题。开发一种有效的结核分枝杆菌疫苗需要更好地了解结核分枝杆菌特异的细胞免疫反应，这对控制疾病至关重要。虽然适应性细胞免疫反应在结核病的宿主控制中是必不可少的，但导致对结核分枝杆菌产生最佳适应性细胞免疫反应所需的许多先天免疫机制仍未确定。更好地了解这一联系对于开发有效的疫苗至关重要。我们最近确定，接触和未接触结核病的人都有粘膜相关不变T细胞(MAIT)，这些细胞是Mtb反应的。MAIT细胞被认为是先天T细胞，因为它们限制表达半不变的Va7.2 T细胞受体(TCR)，并通过非多态的HLA-Ib分子MR1激活。虽然已知MAIT细胞在人类中出现的频率很高，但这些细胞的生理学相关性仍不清楚。我们推测MAIT细胞可能在结核分枝杆菌的控制中发挥作用。我们在人类中发现了ABT细胞受体+CD3+CD4-胸腺细胞的普遍和高频群体，它能在体外直接产生干扰素-g，以响应结核分枝杆菌感染的细胞。最近，我们确定了这些Mtb反应性胸腺细胞的一部分表达Va7.2 TCR。这项应用旨在1)确定MAIT细胞是否代表结核分枝杆菌反应性先天T细胞群，在结核病的先天控制中提供INF-g的早期来源，并帮助获得最佳的适应性Th1免疫反应；2)确定Va7.2+结核分枝杆菌反应性T细胞响应结核杆菌感染细胞的分子机制；3)确定Va7.2+结核分枝杆菌反应性T细胞识别的结核杆菌抗原(S)。这些研究可能有助于更全面地了解结核病免疫的产生，从而促进改进的结核病疫苗的开发。 公共卫生相关性：项目叙述结核病(TB)是全世界传染病发病率和死亡率的最重要原因之一。有助于获得有效免疫反应的先天细胞机制仍有待确定。在我们对人类先天T细胞群体的研究中，我们的目标是更好地了解结核病的免疫反应，从而促进改进的结核病疫苗的开发。

DESCRIPTION (provided by applicant): Project Summary Mycobacterium tuberculosis (Mtb) infects about one third of the population worldwide. An estimated 8 million new cases and 2 million deaths occur annually placing tuberculosis (TB) as a significant health problem. The development of an efficacious vaccine for Mtb will require a better understanding of the Mtb-specific cellular immune response that is critical to control the disease. While the adaptive cellular immune response is essential in the host control of TB, many of the innate immune mechanisms that are required to result in an optimal adaptive cellular immune response to Mtb remain to be characterized. A better understanding of this link is critical in the development of an effective vaccine. We have recently determined that both TB-exposed and unexposed individuals have mucosal associate invariant T cells (MAIT) that are Mtb-reactive. MAIT cells are thought to be innate T cells based on their restricted expression of the semi-invariant Va7.2 T cell receptor (TCR) and their activation via the non-polymorphic HLA-Ib molecule MR1. Although MAIT cells are known to be present at high frequencies in humans the physiological relevance of these cells remains unknown. We hypothesize that MAIT cells may play a role in the control of the bacterium Mycobacterium tuberculosis. We identified a prevalent and high frequency population of abT-cell receptor+ CD3+ CD4- thymocytes in humans that produces IFN-g directly ex vivo in response to Mtb-infected cells. Recently, we determined that a subset of these Mtb-reactive thymocytes expresses the Va7.2 TCR. This application is designed to 1) Determine if MAIT cells represent an Mtb-reactive innate T cell population that can supply an early source of INF-g in the innate control of TB disease as well as providing aid in the acquisition of an optimal adaptive Th1 immune response; 2) Identify the molecular mechanisms by which Va7.2+ Mtb-reactive T cells respond to Mtb-infected cells; 3) Define the Mtb antigen(s) recognized by Va7.2+ Mtb-reactive T cells. These studies may contribute to a more complete understanding of the generation of TB immunity and hence facilitate the development of an improved TB vaccine. PUBLIC HEALTH RELEVANCE: Project Narrative Tuberculosis (TB) is one of the most important causes of infectious morbidity and mortality worldwide. Innate cellular mechanisms that contribute to the acquisition of an effective immune response remain to be defined. In our studies of an innate population of T cells from humans we aim to better understand the immune response to TB and hence facilitate the development of an improved TB vaccine.