Identifying Common T Cell Responses to Major Pathogens in Rhesus Macaques

描述（由申请人提供）：16个不同的NIH研究所投资超过2亿美元用于研究T细胞对猴免疫缺陷病毒（SIV），结核病和流感的反应的项目。细胞CD8+和CD4+ T细胞反应的特异性分别由个体的主要组织相容性复合体（MHC） I类和II类等位基因库决定。猕猴MHC基因的明显复杂性阻碍了研究人员对表位特异性T细胞反应的精细定位。因此，只有少数siv特异性T细胞反应得到了深入的表征，而对于猕猴对流感和卡介苗（目前用于结核病的疫苗）的表位特异性T细胞反应几乎一无所知。这限制了对监测或评估T细胞反应感兴趣的研究人员。值得注意的是，缺乏具有少数MHC等位基因的动物，而这些等位基因可用于siv特异性T细胞反应和试剂（例如MHC：肽四聚体）。我们的实验室最近发现，印度恒河猴的MHC等位基因共享比以前认识到的更为普遍。超过99%的印度恒河猴至少拥有16个常见MHC I类等位基因中的一个，而94%的印度恒河猴至少拥有9个常见MHC II类-DRB等位基因中的一个。在这个项目中，我们将：1)依次感染具有这25个常见MHC等位基因的印度恒河猴流感、卡介苗和SIV。T细胞对这三种病原体的反应将被绘制出来。2)精细定位表位特异性，确定这些CD8+和CD4+反应的MHC限制。3)生产和分发MHC：肽四聚体，用于受25个常见MHC等位基因限制的应答。我们将制作新的四聚体来测量CD8+和CD4+ T细胞对SIV、流感和卡介苗的反应。T细胞表位和MHC肽四聚体将成为研究重大传染病细胞免疫的宝贵资源。我们的团队在猕猴体内研究SIV、流感和卡介苗的细胞免疫和发病机制的专业知识，以及我们在MHC肽四聚体生产和验证方面的经验，使我们有资格承担这个雄心勃勃的项目。

DESCRIPTION (provided by applicant): 16 different NIH institutes invest more than $200,000,000 in projects studying T cell responses to simian immunodeficiency virus (SIV), tuberculosis, and influenza. The specificity of cellular CD8+ and CD4+ T cell responses are determined by an individual's repertoire of major histocompatibility complex (MHC) class I and class II alleles, respectively. The apparent complexity of macaque MHC genetics has discouraged investigators from fine-mapping epitope- specific T cell responses. Consequently, only a small number of SIV-specific T cell responses have been characterized in depth, while nearly nothing is known about epitope-specific T cell responses against influenza and BCG (the current vaccine for tuberculosis) in macaques. This constrains investigators interested in monitoring or evaluating T cell responses. Tellingly, there have been shortages of animals possessing the few MHC alleles for which SIV-specific T cell responses and reagents (e.g., MHC:peptide tetramers) are available. Our laboratory recently discovered that MHC allele sharing in Indian rhesus macaques is more common than previously realized. More than 99% of Indian rhesus macaques possess at least one of 16 common MHC class I alleles, while 94% have at least one of 9 common MHC class II -DRB alleles. In this project, we will: 1) Sequentially infect Indian rhesus macaques possessing these 25 common MHC alleles with influenza, BCG, and SIV. T cell responses against all three pathogens will be mapped. 2) Fine-map the epitope specificity and determine the MHC restriction of these CD8+ and CD4+ responses. 3) Produce and distribute MHC:peptide tetramers for responses restricted by the 25 common MHC alleles. We will make new tetramers to measure both CD8+ and CD4+ T cell responses against SIV, influenza, and BCG. The T cell epitopes and MHC:peptide tetramers will be a valuable resource for investigators studying cellular immunity to major infectious diseases. Our team's expertise studying cellular immunity and pathogenesis to SIV, influenza, and BCG in macaque monkeys and our experience with MHC:peptide tetramer production and validation uniquely qualifies us to undertake this ambitious project.