Protection against disseminated disease following reinfection with Mycobacterium tuberculosis requires CD8+ lymphocytes

Simonson, A. W.; Chao, M. C.; Bothwell, E. G.; Shan, F.; Rodgers, M. A.; Hood, L. E.; Hopkins, F.; Chase, M. R.; Callendrello, A.; Smith, A. A.; Kelly, R. J.; Ameel, C. L.; Klein, E.; Schober, J.; Kracinovsky, K.; Tomko, J. A.; Chishti, H.; Malin, M.; Borish, H. J.; Maiello, P.; Scanga, C. A.; Lin, P. L.; Shalek, A. K.; Fortune, S. M.; Flynn, J. L.

doi:10.64898/2026.10.29.762796

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bioRxiv · 10.64898/2026.10.29.762796

Protection against disseminated disease following reinfection with Mycobacterium tuberculosis requires CD8+ lymphocytes

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Abstract

Concomitant immunity is protective adaptive immunity conferred by pre-existing infection against subsequent exposures. This phenomenon is effective in the context of human tuberculosis (TB) and has been successfully recapitulated in non-human primates (NHPs). We previously demonstrated that depletion of CD4 T cells prior to secondary challenge with Mycobacterium tuberculosis (Mtb) only partially abrogated protection, implicating a critical role for additional cell types. Here, we describe the effects of depleting CD8 expressing cells in this model. CD4+ T cells in the airway were unable to compensate for lost cytotoxicity due to CD8 depletion. Contrary to the results of CD4 depletion, CD8 depleted animals exhibited a unique inability to limit Mtb dissemination, with significant lymph node involvement despite a short 4-week infection. These data suggest that concomitant immunity relies on non-redundant roles played by CD8+ lymphocytes. Thus, future vaccines should be designed to induce effective responses by both CD4+ and CD8+ populations to maximize efficacy.

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Simonson, A. W., Chao, M. C., Bothwell, E. G., Shan, F., Rodgers, M. A., Hood, L. E., Hopkins, F., Chase, M. R., Callendrello, A., Smith, A. A., Kelly, R. J., Ameel, C. L., Klein, E., Schober, J., Kracinovsky, K., Tomko, J. A., Chishti, H., Malin, M., Borish, H. J., Maiello, P., Scanga, C. A., Lin, P. L., Shalek, A. K., Fortune, S. M., Flynn, J. L.. 2026-11-03. Protection against disseminated disease following reinfection with Mycobacterium tuberculosis requires CD8+ lymphocytes. https://doi.org/10.64898/2026.10.29.762796

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