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200，000，000美元用于研究T细胞对猿免疫缺陷病毒（SIV），结核病和流感的反应的项目。细胞CD 8+和CD 4 + T细胞应答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遗传学的明显复杂性阻碍了研究人员对表位特异性T细胞应答的精细定位。因此，只有少量的SIV特异性T细胞反应已被深入表征，而几乎没有什么是已知的表位特异性T细胞对猕猴流感和卡介苗（目前的结核病疫苗）的反应。这限制了对监测或评估T细胞应答感兴趣的研究人员。很明显，缺乏具有少数MHC等位基因的动物，SIV特异性T细胞应答和试剂（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意识到的更常见。超过99%的印度恒河猴具有16种常见的MHC I类等位基因中的至少一种，而94%具有9种常见的MHC II类-DRB等位基因中的至少一种。在这个项目中，我们将：1）用流感病毒、卡介苗和SIV依次感染具有这25个常见MHC等位基因的印度恒河猴。将绘制针对所有三种病原体的T细胞应答。2)精细定位表位特异性并确定这些CD 8+和CD 4+应答的MHC限制。3)产生和分配MHC：肽四聚体，用于受25种常见MHC等位基因限制的反应。我们将制造新的四聚体来测量CD 8+和CD 4 + T细胞对SIV、流感和BCG的反应。T细胞表位和MHC：肽四聚体将为研究人员研究主要传染病的细胞免疫提供宝贵的资源。我们团队在猕猴中研究SIV、流感和BCG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一雄心勃勃的项目。

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.