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

The response of gamma delta (gamma delta) T cells in the acute versus chronic phases of the same infection is unclear. How gamma delta 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 gamma delta T cells from a South African ado-lescent cohort and show that a unique CD8+ gamma delta 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+ gamma delta T cells comprise a highly focused TCR repertoire, with clonotypes that are Mycobacterium specific but not phosphoantigen reactive. Using multi -parametric single-cell pseudo-time trajectory analysis, we identified the differentiation paths that these CD8+ gamma delta T cells follow to develop into effectors in this infection state. Last, we found that circulating CD8+ gamma delta T cells also expand in other chronic inflammatory conditions, including cardiovascular disease and cancer, suggesting that persistent antigenic exposure may drive similar gamma delta T cell effector programs and differentiation fates.