Single-cell profiling of tuberculosis lung granulomas reveals functional lymphocyte signatures of bacterial control

Biology Biology
Cell Atlas Cell Atlas
Genomics Genomics
Immunology Immunology
Infectious Disease Infectious Disease
Alex K. Shalek Alex K. Shalek
Conner Kummerlowe Conner Kummerlowe
José Ordovas-Montañes José Ordovas-Montañes
Marc Wadsworth II Marc Wadsworth II
Sarah Nyquist Sarah Nyquist
Travis Hughes Travis Hughes

Gideon et al.▾ Gideon, H.P., Hughes, T.K., Wadsworth II, M.H., Tu, A.A., Gierahn, T.M., Hopkins, F.H., Wei, J., Kummerlowe, C., Grant, N.L., Nargan, K., Phuah, J., Borish, H.J., Maiello, P., White, A.G., Ganchua, S.K.C., Myers, A., Ameel, C., Cochran, C.T., Nyquist, S.K., Peters, J.M., Tomko, J.A., Frye Jr., L.J., Rosenberg, J., Shih, A., Chao, M., Scanga, C., Ordovas-Montanes, J., Berger, B., Mattila, J.T., Madansein, R., Love, J.C., Bryson, B.D., Lin, P.L., Leslie, A., Behar, S.M., Flynn, J.L., Fortune, S.M., Shalek, A.K.


October, 2020


In humans and nonhuman primates, Mycobacterium tuberculosis lung infection yields a complex multicellular structure: the tuberculosis granuloma. All granulomas are not equivalent, however, even within the same host: in some, local immune activity promotes bacterial clearance, while in others, it allows persistence or outgrowth. Here, we used single-cell RNA-sequencing to define holistically cellular responses associated with control in cynomolgus macaques. Granulomas that facilitated bacterial killing contained significantly higher proportions of CD4+ and CD8+ T cells expressing hybrid Type1-Type17 immune responses or stem-like features and CD8-enriched T cells with specific cytotoxic functions; failure to control correlated with mast cell, plasma cell and fibroblast abundance. Co-registering these data with serial PET-CT imaging suggests that a degree of early immune control can be achieved through cytotoxic activity, but that more robust restriction only arises after the priming of specific adaptive immune responses, defining new targets for vaccination and treatment.