Abstract
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.
Highlights
Tuberculosis(TB) remains one of the leading causes of morbidity and mortality worldwide among infectious diseases, and has become increasingly prevalent and deadly as a result of the emergence of multi-drug resistant (MDR) TB and HIV/AIDS pandemic [1,2]
We determined whether earlier expansion/differentiation of Vc2Vd2 T cells during M. tuberculosis (Mtb) infection increased resistance to TB in macaques
The repeated Picostim/IL-2 treatment at day 15 after Mtb infection led to a subtle increase in the mean number of blood Vc2Vd2 T cells compared to the level at day 9, the time in which numbers of Vc2Vd2 T cells remained higher than baseline despite declining from the peak expansion following the initial treatment(Fig. 1a,1b)
Summary
Tuberculosis(TB) remains one of the leading causes of morbidity and mortality worldwide among infectious diseases, and has become increasingly prevalent and deadly as a result of the emergence of multi-drug resistant (MDR) TB and HIV/AIDS pandemic [1,2]. Given the possibility that TB patients usually have immune dysfunction, immune intervention regulating or enhancing anti-TB immune responses may be beneficial for clinical treatment of TB or MDR-TB. In-depth studies of Mtbspecific T effector cells may facilitate our understanding of anti-TB immune mechanisms and help identify potential immune intervention for drug-resistant TB. Vc2Vd2 T cells exist only in primates, constitute 65–90% of total human circulating cd T cells, and regulate or contribute to both innate and adaptive-like immune responses in infections [5,6,7,8,9]. Our decades-long studies in non-human primate models contribute to illustrating biology and immune responses of human Vc2Vd2 T cells in Mtb and other
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