NK-like CD8 <sup>+</sup> γδ T cells are expanded in persistent <i>Mycobacterium tuberculosis</i> infection
Roshni Roy Chowdhury, John R. Valainis, Megha Dubey, Lotta von Boehmer, Elsa Solà, Julie Wilhelmy, Jing Guo, Oliver Kask, Mané Ohanyan, Meng Sun, Huang Huang, Xianxi Huang, Patricia K. Nguyen, Thomas J. Scriba, Mark M. Davis, Sean C. Bendall, Yueh‐hsiu Chien
Abstract
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 Mycobacterium tuberculosis (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 Mycobacterium 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.