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SummaryγδT cells contribute to host immune defense uniquely; but how they function in different stages (e.g., acute versus chronic) of a specific infection remains unclear. As the role ofγδT cells in early, activeMycobacterium tuberculosis(Mtb) infection is well documented, we focused on elucidating theγδT cell response in persistent or controlled Mtb infection. Systems analysis of circulatingγδT cells from a South African adolescent cohort identified a distinct population of CD8+γδT cells that expanded in this state. These cells had features indicative of persistent antigenic exposure but were robust cytolytic effectors and cytokine/chemokine producers. While theseγδT cells displayed an attenuated response to TCR-mediated stimulation, they expressed Natural Killer (NK) cell receptors and had robust CD16 (FcγRIIIA)-mediated cytotoxic response, suggesting alternative ways forγδT cells to control this stage of the infection. Despite this NK- like functionality, the CD8+γδT cells consisted of highly expanded clones, which utilized TCRs with different Vγ/δpairs. Theses TCRs could respond to an Mtb-lysate, but not to phosphoantigens, which are components of Mtb-lysate that activateγδT cells in acute Mtb infection, indicating that the CD8+γδT cells were induced in a stage-specific, antigen-driven manner. Indeed, trajectory analysis showed that theseγδT cells arose from naive cells that had traversed distinct differentiation paths in this infection stage. Importantly, increased levels of CD8+γδT cells were also found in other chronic inflammatory conditions, including cardiovascular disease and cancer, suggesting that persistent antigenic exposure may lead to similarγδT cell responses.