NK-like CD8 + γδ T cells are expanded in persistent Mycobacterium tuberculosis infection

• Published in: Science immunology 2023-03, Vol.8 (81), p.eade3525
• Main Authors: Roy Chowdhury, Roshni, Valainis, John R, Dubey, Megha, von Boehmer, Lotta, Sola, Elsa, Wilhelmy, Julie, Guo, Jing, Kask, Oliver, Ohanyan, Mane, Sun, Meng, Huang, Huang, Huang, Xianxi, Nguyen, Patricia K, Scriba, Thomas J, Davis, Mark M, Bendall, Sean C, Chien, Yueh-Hsiu
• Format: Article
• Language: English
• Subjects: Adolescent; CD8-Positive T-Lymphocytes; Humans; Intraepithelial Lymphocytes; Mycobacterium tuberculosis; Receptors, Antigen, T-Cell, gamma-delta; Tuberculosis
• ISSN: 2470-9468; 2470-9468
• DOI: 10.1126/sciimmunol.ade3525

The response of gamma delta (γδ) T cells in the acute versus chronic phases of the same infection is unclear. How γδ T cells function in acute (Mtb) infection is well characterized, but their response during persistent Mtb infection is not well understood, even though most infections with Mtb manifest as a chronic, clinically asymptomatic state. Here, we analyze peripheral blood γδ T cells from a South African adolescent cohort and show that a unique CD8 γδ T cell subset with features of "memory inflation" expands in chronic Mtb infection. These cells are hyporesponsive to T cell receptor (TCR)-mediated signaling but, like NK cells, can mount robust CD16-mediated cytotoxic responses. These CD8 γδ T cells comprise a highly focused TCR repertoire, with clonotypes that are specific but not phosphoantigen reactive. Using multiparametric single-cell pseudo-time trajectory analysis, we identified the differentiation paths that these CD8 γδ T cells follow to develop into effectors in this infection state. Last, we found that circulating CD8 γδ T cells also expand in other chronic inflammatory conditions, including cardiovascular disease and cancer, suggesting that persistent antigenic exposure may drive similar γδ T cell effector programs and differentiation fates.