Role of antigen-specific T cell responses in the control of TB

U19申请的整体描述(由申请人提供)：我们的TB RU专注于对结核分枝杆菌(Mtb)的免疫，以检验潜在结核病感染(LTBI)作为一系列细菌和免疫学状态存在的总体假设，即至少可以区分和对应三种免疫学状态：1)既往但已清除的结核分枝杆菌感染；2)进展为活动期疾病的风险较低的稳定的LTBI；或3)进展为活动期结核病的高风险的LTBI。为了验证这一假设，我们将识别T细胞特征，包括识别的抗原的广度、表型和结核分枝杆菌特异性CD4和CDB T细胞的功能，以及与在人类和实验感染的非人类灵长类动物中进行的独特前瞻性研究确定的结果的相关性。除了独特的前瞻性研究外，我们还将使用一种新型的“反应谱分析”(RSA)，其中包括60个经过战略选择的结核分枝杆菌抗原和表位多肽，以分析具有不同风险和进展为活动性结核病的LTBI受试者的抗原识别的定量广度和特定模式。此外，RSA中确定的抗原和表位将被用于设计人类白细胞抗原多肽四聚体，用于高分辨率研究MTB表位特异性T细胞的表型和功能能力。这些研究的结果使用了包括质量细胞术(CyTOF)在内的先进技术，与RSA的结果一起，将被用于识别不同风险类别的LTBI的T细胞特征。某些经TE验证的T细胞特征将对应于有效的免疫反应，这些免疫反应是结核病疫苗开发的理想目标，而其他特征将有助于识别患有LTBI的人，这些人进展为活动性结核病的风险最高，因此可以优先对这些人进行预防干预。我们的人体研究将在美国佐治亚州亚特兰大进行，并与肯尼亚医学研究所/美国疾病控制中心(KEMRI/CDC)的研究人员合作；对非人类灵长类动物结核病的研究将由两个国家灵长类研究中心(Yerkes和Tulane)的专家完成。我们组建的小组拥有广泛的知识和专业知识，并准备增进对结核病免疫的了解，为消除结核病作出贡献。

DESCRIPTION OF THE OVERALL U19 APPLICATION (provided by applicant): Our TBRU focuses on immunity to M. tuberculosis (Mtb), to test the overall hypothesis that latent TB infection (LTBI) exists as a spectrum of bacterial and immunologic states, that at least three immunological states can be distinguished and correspond to: 1) past, but cleared Mtb infection; 2] stable LTBI with a low risk of progression to active disease; or 3) LTBI with a high risk of progression to active TB disease. To test this hypothesis, we will identify T cell signatures, consisting of the breadth of antigens recognized, the phenotypes, and the functions of Mtb-specific CD4 and CDB T cells, with correlations to outcomes determined in unique prospective studies in humans and in experimentally-infected nonhuman primates. In addition to unique prospective studies, we will use a novel 'Response Spectrum Assay' (RSA) that includes >60 strategically-selected Mtb antigens and epitope peptides, to assay the quantitative breadth and specific pattern of antigen recognition in LTBI subjects with distinct risks and rates of progression to active TB. In addition, antigens and epitopes identified in the RSA will be used to design HLA-peptide tetramers for high-resolution studies of the phenotypes and functional capabilities of Mtb epitope-specific T cells. The results of these studies, which employ advanced technologies including mass cytometry (CyTOF), together with the results of the RSA, will be used to identify T cell signatures characteristic of distinct risk categories of LTBI. Certain of te validated T cell signatures will correspond to efficacious immune responses that are desirable targets of TB vaccine development, while others will be useful for identifying individuals with LTBI that are at highest risk of progression to active TB, so these individuals can be prioritized for preventive interventions. Our human studies will be conducted in Atlanta, GA, USA, and in collaboration with investigators at the Kenya Medical Research Institute/U.S. Centers for Disease Control (KEMRI/CDC); studies of TB in nonhuman primates will be done by experts at two national primate research centers (Yerkes and Tulane). The team we have assembled possesses a wide range of knowledge and expertise, and is poised to generate improved understanding of TB immunity to contribute to the elimination of TB.