Host genetic diversity, T cell responses, and outcomes of TB

结核病(TB)每年导致的死亡人数超过包括艾滋病毒在内的任何其他传染病。其中 控制和消除结核病的最优先需要是一种或多种有效的疫苗。然而， 有效疫苗的开发受阻于对其发病机制和相互关系的了解不足 对结核分枝杆菌的保护性免疫。协同杂交小鼠品系CC001和CC001的证据 CC002比C57BL/6(B6)小鼠更能清除结核分枝杆菌，提供了更好的机会 在一个高度易处理和经济的实验模型中了解结核病的免疫机制。二 主要证据为本申请中提出的研究提供了基础：1)更好的控制 CC001和CC002(与B6相比)小鼠在适应性免疫后观察到结核分枝杆菌 2)CD4T细胞是小鼠结核病获得性免疫的基本和主要贡献者， 人类。因此，我们建议使用创新的新工具进行深入的比较研究，以检验假设 结核分枝杆菌感染CC001和CC002小鼠肺内CD4T细胞功能优于 并确定其功能优势的机制基础。我们的研究将测试 假设在CC001和/或CC002小鼠中，CD4T细胞：1)识别更广泛的抗原；2)是 生成的数量更多；3)更有效的流量；4)由更多样化的克隆类型组成；5)表现出独特的 功能特性和/或6)在体内以更高的频率被激活，以使它们更有效地对抗 结核分枝杆菌对B6小鼠的抑制作用大于B6小鼠。我们将应用于这些研究的创新工具包括一种新方法 在结核分枝杆菌蛋白质组中发现T细胞表位的创新方法 在单细胞基础上鉴定表位特异性、T细胞抗原受体序列和转录图谱； 和一种新的报告小鼠品系，用于定量体内抗原和TCR依赖的CD4T细胞激活 感染的地方。我们的研究将产生CC001和CC001免疫表型的定量数据 CC002小鼠，说明他们对结核分枝杆菌的优越控制，并将确定 免疫优势机制(S)在两品系小鼠中有相似之处，也有不同之处。此外，我们的研究 旨在提供量化数据，以便于对未来研究中产生的小鼠进行表型鉴定 为了定位和鉴定CC001和CC002小鼠的结核病免疫优势的因果遗传变异， 最终确定有助于结核病免疫的分子机制。我们预计，我们的结果将 为人类的翻译研究提供了基础，并将有助于开发更多 治疗结核病的有效疫苗。

Tuberculosis (TB) kills more humans every year than does any other infectious disease, including HIV. Among the highest priority needs for control and elimination of TB is one or more efficacious vaccines. However, development of efficacious vaccines is impeded by insufficient knowledge of the mechanisms and correlates of protective immunity to M. tuberculosis. The evidence that the Collaborative Cross mouse strains, CC001 and CC002, are more able to clear M. tuberculosis than are C57BL/6 (B6) mice, provides the opportunity to better understand the mechanisms of immunity to TB in a highly tractable and economical experimental model. Two major lines of evidence provide the basis for the studies proposed in this application: 1) the superior control of M. tuberculosis in CC001 and CC002 (compared to B6) mice is observed after development of adaptive immune responses; 2) CD4 T cells are essential and dominant contributors to adaptive immunity to TB in mice and humans. Therefore, we propose intensive comparative studies using innovative new tools to test the hypotheis that CD4 T cells in the lungs of M. tuberculosis-infected CC001 and CC002 mice are functionally superior to those in B6 mice, and to determine the mechanistic basis of their functional superiority. Our studies will test the hypotheses that in CC001 and/or CC002 mice, CD4 T cells: 1) recognize a broader spectrum of antigens; 2) are generated in larger numbers; 3) traffic more effectively; 4) consist of more diverse clonotypes; 5) exhibit distinct functional properties and/or 6) are activated at higher frequencies in vivo, to make them more effective against M. tuberculosis than in B6 mice. The innovative tools that we will apply to these studies include a new method for T cell epitope discovery in the proteome of M. tuberculosis, an innovative method for simultaneously identifying epitope specificity, T cell antigen receptor sequence, and transcriptional profiles on a single-cell basis; and a new strain of reporter mice for quantitating antigen- and TCR-dependent CD4 T cell activation in vivo at the site of infection. Our studies will generate quantitative data on the immunological phenotypes of CC001 and CC002 mice that account for their superior control of M. tuberculosis, and will determine whether the mechanism(s) of superior immunity in the two strains of mice are similar or are distinct. Furthermore, our studies are designed to provide quantitative data that will facilitate phenotyping of mice generated during future studies to map and identify the causal genetic variants that account for superior TB immunity in CC001 and CC002 mice, to ultimately define molecular mechanisms that contribute to TB immunity. We anticipate that our results will provide a basis for translational studies in humans, and that they will contibute to development of more efficacious vaccines for TB.