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

结核病每年造成的死亡人数超过包括艾滋病毒在内的任何其他传染病。之间 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，在这方面， 有效疫苗的开发由于对免疫反应的机制和相关因素的认识不足而受到阻碍。 对M.结核协作杂交小鼠品系CC001和CC002的证据表明， CC002，更能清除M。结核病比C57BL/6（B6）小鼠，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对结核病的免疫机制。两 主要的证据线为本申请中提出的研究提供了基础：1）对以下疾病的上级控制 M. CC001和CC002（与B6相比）小鼠在适应性免疫发展后观察到结核病 2）CD4 T细胞是小鼠对TB的适应性免疫的重要和主要贡献者， 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，以验证假设 M.结核感染的CC001和CC002小鼠在功能上优于 这些在B6小鼠，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，CD4 T细胞：1）识别更广谱的抗原; 2） 产生的数量更大; 3）交通更有效; 4）由更多样化的克隆型组成; 5）表现出不同的 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 M. B6小鼠的肺结核。我们将应用于这些研究的创新工具包括一种新方法， 在M.结核病，一种创新的方法， 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谱; 和一种新的报告小鼠品系，用于在体内定量抗原和TCR依赖性CD4 T细胞活化， 感染的部位。我们的研究将产生关于CC001免疫表型的定量数据， CC002小鼠对M.结核病，并将确定是否 两种小鼠品系中的上级免疫机制是相似的或不同的。此外，我们的研究 旨在提供定量数据，以促进在未来研究中产生的小鼠表型分析 为了定位和鉴定导致CC 001和CC 002小鼠中上级TB免疫力的致病性遗传变异体， 最终确定有助于结核免疫的分子机制。我们预计，我们的结果将 为人类的转化研究提供了基础，它们将有助于开发更多的 有效的结核病疫苗。

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.