Dominant Vγ2Vδ2 T-cell subset exist only in primates, and recognize phosphoantigen from selected pathogens including M. tuberculosis(Mtb). In vivo function of Vγ2Vδ2 T cells in tuberculosis remains unknown. We conducted mechanistic studies to determine whether earlier expansion/differentiation of Vγ2Vδ2 T cells during Mtb infection could increase immune resistance to tuberculosis in macaques. Phosphoantigen/IL-2 administration specifically induced major expansion and pulmonary trafficking/accumulation of phosphoantigen-specific Vγ2Vδ2 T cells, significantly reduced Mtb burdens and attenuated tuberculosis lesions in lung tissues compared to saline/BSA or IL-2 controls. Expanded Vγ2Vδ2 T cells differentiated into multifunctional effector subpopulations capable of producing anti-TB cytokines IFNγ, perforin and granulysin, and co-producing perforin/granulysin in lung tissue. Mechanistically, perforin/granulysin-producing Vγ2Vδ2 T cells limited intracellular Mtb growth, and macaque granulysin had Mtb-bactericidal effect, and inhibited intracellular Mtb in presence of perforin. Furthermore, phosphoantigen/IL2-expanded Vγ2Vδ2 T effector cells produced IL-12, and their expansion/differentiation led to enhanced pulmonary responses of peptide-specific CD4+/CD8+ Th1-like cells. These results provide first in vivo evidence implicating that early expansion/differentiation of Vγ2Vδ2 T effector cells during Mtb infection increases resistance to tuberculosis. Thus, data support a rationale for conducting further studies of the γδ T-cell-targeted treatment of established TB, which might ultimately help explore single or adjunctive phosphoantigen expansion of Vγ2Vδ2 T-cell subset as intervention of MDR-tuberculosis or HIV-related tuberculosis.
Tuberculosis(TB), caused by Mycobacterium tuberculosis(Mtb), remains a leading cause of morbidity and mortality worldwide. While CD4+/CD8+ T cells are protective, role of γδ T cells in TB and other infections remains unknown in humans. Vγ2Vδ2 T cells exist only in primates, represent a dominant circulating γδ T-cell subpopulation, and recognize phosphoantigen from Mtb and some selected pathogens. Here, we determined whether earlier expansion/differentiation of Vγ2Vδ2 T cells during Mtb infection increased resistance to TB in macaques. Phosphoantigen plus IL-2 administration induced expansion and pulmonary accumulation of Vγ2Vδ2 T cells, significantly reduced Mtb counts and attenuated TB lesions in lung tissues. Expanded Vγ2Vδ2 T cells produced anti-TB cytokines IFNγ, perforin and granulysin, and co-produced perforin and granulysin in lung tissue. Perforin/granulysin-co-producing Vγ2Vδ2 T cells limited intracellular Mtb growth, and macaque granulysin killed Mtb bacteria, and inhibited intracellular Mtb in presence of perforin. Furthermore, expansion of Vγ2Vδ2 T effectors enhanced pulmonary responses of peptide-specific CD4+/CD8+ T cells, which correlated with the ability of Vγ2Vδ2 T effector cells to produce IL-12. These results provide first evidence implicating a protective role of Vγ2Vδ2 T effector cells in TB, supporting a rationale to explore Vγ2Vδ2 T-cell-targeted treatment of drug-resistant TB or HIV-related TB.