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

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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.