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

我们的TBRU专注于对结核分枝杆菌(Mtb)的免疫，以检验潜伏结核病的总体假设 感染(LTBI)以细菌和免疫学状态的谱系存在，至少有三种免疫学状态 状态可被区分并对应于：1)过去，但已清除结核分枝杆菌感染；2)稳定的LTBI与低 进展为活动性疾病的风险；或3)LTBI，进展为活动性结核病的高风险。为了测试 在这个假设中，我们将识别T细胞特征，包括识别的抗原的广度， 结核分枝杆菌特异性CD4和CDB T细胞的表型和功能与预后的相关性 在人类和实验感染的非人类灵长类动物中进行的独特的前瞻性研究中确定了这一点。在……里面 除了独特的前瞻性研究外，我们还将使用一种新的‘反应频谱分析’(RSA)，它包括 &gt；60精心挑选的结核分枝杆菌抗原和表位多肽，以测定定量的广度和特异性 具有不同风险和进展到活动性结核病的LTBI受试者的抗原识别模式。在……里面 此外，RSA中确定的抗原和表位将用于设计用于 对结核分枝杆菌表位特异性T细胞表型和功能的高分辨率研究。这个 这些研究的结果，使用了先进的技术，包括质量细胞分析(CyTOF)，以及 根据RSA的结果，将用于识别不同风险类别的T细胞签名特征 LTBI的。某些有效的T细胞特征将与有效的免疫反应相对应 结核病疫苗开发的理想目标，而其他目标将有助于识别患有LTBI的个人 进展为活动性结核病的风险最高的人，因此可以优先考虑这些人的预防 干预措施。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； 关于非人类灵长类动物结核病的研究将由两个国家灵长类动物研究中心的专家完成 (耶克斯和杜兰)。我们组建的团队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，为消除结核病做出贡献。

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.