CD8+ lymphocytes are critical for early control of tuberculosis in macaques

Computational Methods Computational Methods
Infectious Disease Infectious Disease
Medicine Medicine
Alex K. Shalek Alex K. Shalek
Josh Bromley Josh Bromley
Marc Wadsworth II Marc Wadsworth II
Sarah Nyquist Sarah Nyquist
Travis Hughes Travis Hughes

Winchell et al.▾ Winchell, C.G., Nyquist, S.K., Chao, M.C., Maiello, P., Myers, A.J., Hopkins, F., Chase, M., Gideon, H.P., Patel, K.V., Bromley, J.D., Simonson, A.W., Floyd'O'Sullivan, R., Wadsworth, M., Rosenberg, J.M., Uddin, R., Hughes, T., Kelly, R.J., Griffo, J., Tomko, J., Klein, E., Berger, B, Scanga, C.A., Mattila, J., Fortune, S.M., Shalek, A.K., Lin, P.L., Flynn, J.L.,

Journal of Experimental Medicine , Volume 220

October, 2023


The functional role of CD8+ lymphocytes in tuberculosis remains poorly understood. We depleted innate and/or adaptive CD8+ lymphocytes in macaques and showed that loss of all CD8α+ cells (using anti-CD8α antibody) significantly impaired early control of Mycobacterium tuberculosis (Mtb) infection, leading to increased granulomas, lung inflammation, and bacterial burden. Analysis of barcoded Mtb from infected macaques demonstrated that depletion of all CD8+ lymphocytes allowed increased establishment of Mtb in lungs and dissemination within lungs and to lymph nodes, while depletion of only adaptive CD8+ T cells (with anti-CD8β antibody) worsened bacterial control in lymph nodes. Flow cytometry and single-cell RNA sequencing revealed polyfunctional cytotoxic CD8+ lymphocytes in control granulomas, while CD8-depleted animals were unexpectedly enriched in CD4 and γδ T cells adopting incomplete cytotoxic signatures. Ligand-receptor analyses identified IL-15 signaling in granulomas as a driver of cytotoxic T cells. These data support that CD8+ lymphocytes are required for early protection against Mtb and suggest polyfunctional cytotoxic responses as a vaccine target.