Chen, Crystal Y.Yao, ShuyuHuang, DanWei, HuiyongSicard, HeleneZeng, GuchengJomaa, HassanLarsen, Michelle H.Jacobs, William R.Wang, RichardLetvin, NormanShen, YunQiu, LiyouShen, LingChen, Zheng W.2014-03-012013Chen, C. Y., S. Yao, D. Huang, H. Wei, H. Sicard, G. Zeng, H. Jomaa, et al. 2013. “Phosphoantigen/IL2 Expansion and Differentiation of Vγ2Vδ2 T Cells Increase Resistance to Tuberculosis in Nonhuman Primates.” PLoS Pathogens 9 (8): e1003501. doi:10.1371/journal.ppat.1003501. http://dx.doi.org/10.1371/journal.ppat.1003501.1553-7366http://nrs.harvard.edu/urn-3:HUL.InstRepos:11855838Dominant 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.en-USBiologyImmunologyImmunityImmunity to InfectionsJournal Article2014-03-0110.1371/journal.ppat.1003501