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.
Tuberculosis (TB) remains a leading killer among infectious diseases, and a better TB vaccine is urgently needed. The critical components and mechanisms of vaccine-induced protection against Mycobacterium tuberculosis (Mtb) remain incompletely defined. Our previous studies demonstrate that Vγ2Vδ2 T cells specific for (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) phosphoantigen are unique in primates as multifunctional effectors of immune protection against TB infection. Here, we selectively immunized Vγ2Vδ2 T cells and assessed the effect on infection in a rhesus TB model. A single respiratory vaccination of macaques with an HMBPP-producing attenuated Listeria monocytogenes (Lm ΔactA prfA*) caused prolonged expansion of HMBPP-specific Vγ2Vδ2 T cells in circulating and pulmonary compartments. This did not occur in animals similarly immunized with an Lm ΔgcpE strain, which did not produce HMBPP. Lm ΔactA prfA* vaccination elicited increases in Th1-like Vγ2Vδ2 T cells in the airway, and induced containment of TB infection after pulmonary challenge. The selective immunization of Vγ2Vδ2 T cells reduced lung pathology and mycobacterial dissemination to extrapulmonary organs. Vaccine effects coincided with the fast-acting memory-like response of Th1-like Vγ2Vδ2 T cells and tissue-resident Vγ2Vδ2 effector T cells that produced both IFN-γ and perforin and inhibited intracellular Mtb growth. Furthermore, selective immunization of Vγ2Vδ2 T cells enabled CD4+ and CD8+ T cells to mount earlier pulmonary Th1 responses to TB challenge. Our findings show that selective immunization of Vγ2Vδ2 T cells can elicit fast-acting and durable memory-like responses that amplify responses of other T cell subsets, and provide an approach to creating more effective TB vaccines.