Immunization of Vγ2Vδ2 T cells programs sustained effector memory responses that control tuberculosis in nonhuman primates

Significance Despite the urgent need for a better tuberculosis (TB) vaccine, relevant protective mechanisms remain unknown. We previously defined protective phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP)–specific Vγ2Vδ2 T cells as a unique subset in primates, and, here, we immunized them selectively for protection against TB. A single respiratory vaccination of macaques with attenuated HMBPP-producing Listeria monocytogenes (Lm ΔactA prfA *), but not an HMBPP-lacking ΔgcpE Listeria strain, expanded Vγ2Vδ2 T cells, elicited Th1-like Vγ2Vδ2 T cell responses, and reduced TB infection/pathology after moderate-dose TB challenge. Such protection correlated with rapid memory-like, Th1-like Vγ2Vδ2 T cell responses, the presence of tissue-resident Vγ2Vδ2 T effectors coproducing IFN-γ/perforin and inhibiting intracellular Mycobacterium tuberculosis growth, and enhanced CD4 + /CD8 + T cell responses. These findings establish a concept incorporating immunization of human Vγ2Vδ2 T cells for TB vaccine development.