Mechanisms of recognition by Mycobacterium tuberculosis-reactive thymocytes

项目概述结核分枝杆菌（Mtb）感染了全球约三分之一的人口。据估计，每年有800万新发病例和200万人死亡，使结核病成为一个重大健康问题。开发有效的结核分枝杆菌疫苗将需要更好地了解结核分枝杆菌特异性细胞免疫反应，这对控制该疾病至关重要。虽然适应性细胞免疫应答在宿主控制结核中至关重要，但许多导致最佳适应性细胞免疫应答所需的先天免疫机制仍有待研究。更好地了解这一联系对于研制有效疫苗至关重要。我们最近确定结核暴露和未暴露的个体都有粘膜相关不变T细胞（MAIT），它们是mmb反应性的。MAIT细胞被认为是先天T细胞，基于它们半不变性v7.2 T细胞受体（TCR）的受限表达和它们通过非多态性HLA-Ib分子MR1激活。尽管已知MAIT细胞在人类中以高频率存在，但这些细胞的生理相关性尚不清楚。我们假设MAIT细胞可能在结核分枝杆菌的控制中发挥作用。我们在人类胸腺细胞中发现了一种普遍和高频率的abt细胞受体+ CD3+ CD4-胸腺细胞群，它们直接在体外对mtb感染的细胞产生IFN-g。最近，我们确定这些mmb反应性胸腺细胞的一个子集表达Va7.2 TCR。该应用程序旨在1)确定MAIT细胞是否代表mtb反应性先天T细胞群，该细胞群可以在TB疾病的先天控制中提供nf -g的早期来源，并为获得最佳适应性Th1免疫应答提供帮助；2)明确v7.2 + mtb反应性T细胞对mtb感染细胞应答的分子机制；3)确定v7.2 + Mtb反应性T细胞识别的Mtb抗原。这些研究可能有助于更全面地了解结核免疫的产生，从而促进改进结核疫苗的开发。

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.