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

我们的TBRU专注于对M的免疫。结核病（Mtb），以检验潜伏性结核病的总体假设， 感染（LTBI）作为一系列细菌和免疫状态存在，至少有三种免疫状态 状态可以区分并对应于：1）过去的，但清除的Mtb感染; 2）稳定的LTBI，具有低的 进展为活动性疾病的风险;或3）具有进展为活动性TB疾病的高风险的LTBI。测试 根据这一假设，我们将识别T细胞特征，包括识别的抗原的宽度， 表型，Mtb特异性CD 4和CDB T细胞的功能，以及与结果的相关性 在人类和实验感染的非人灵长类动物中进行的独特前瞻性研究中确定。在 除了独特的前瞻性研究外，我们还将使用一种新的“反应谱分析”（RSA）， >60种战略性选择的Mtb抗原和表位肽，以测定定量宽度和特异性 LTBI受试者的抗原识别模式，具有不同的风险和进展为活动性TB的速率。在 此外，RSA中鉴定的抗原和表位将用于设计HLA-肽四聚体， Mtb表位特异性T细胞的表型和功能能力的高分辨率研究。的 这些研究采用了包括质谱仪（CyTOF）在内的先进技术， 与RSA的结果，将用于识别不同风险类别的T细胞特征 关于LTBI某些经验证的T细胞特征将对应于有效的免疫应答， 结核病疫苗开发的理想目标，而其他将用于识别LTBI个体 发展为活动性结核病的风险最高，因此这些人可以优先接受预防性治疗， 干预措施。我们的人体研究将在美国佐治亚州亚特兰大市进行，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; 两个国家灵长类动物研究中心的专家将在非人类灵长类动物中进行结核病研究 （Yerkes and Tulane）我们组建的团队拥有广泛的知识和专业知识， 并准备提高对结核病免疫力的认识，以促进消除结核病。

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 progreission 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 the 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.