Phosphoantigen/IL2 expansion and differentiation of V?2V?2 T cells increase resistance to tuberculosis in nonhuman primates.

ABSTRACT: Dominant V?2V?2 T-cell subset exist only in primates, and recognize phosphoantigen from selected pathogens including M. tuberculosis(Mtb). In vivo function of V?2V?2 T cells in tuberculosis remains unknown. We conducted mechanistic studies to determine whether earlier expansion/differentiation of V?2V?2 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 V?2V?2 T cells, significantly reduced Mtb burdens and attenuated tuberculosis lesions in lung tissues compared to saline/BSA or IL-2 controls. Expanded V?2V?2 T cells differentiated into multifunctional effector subpopulations capable of producing anti-TB cytokines IFN?, perforin and granulysin, and co-producing perforin/granulysin in lung tissue. Mechanistically, perforin/granulysin-producing V?2V?2 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 V?2V?2 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 V?2V?2 T effector cells during Mtb infection increases resistance to tuberculosis. Thus, data support a rationale for conducting further studies of the ?? T-cell-targeted treatment of established TB, which might ultimately help explore single or adjunctive phosphoantigen expansion of V?2V?2 T-cell subset as intervention of MDR-tuberculosis or HIV-related tuberculosis.

SUBMITTER: Chen CY 

PROVIDER: S-EPMC3744401 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature