Cytokine requirements for the differentiation and expansion of IL-17A- and IL-22-producing human Vgamma2Vdelta2 T cells.

Human gammadelta T cells expressing the Vgamma2Vdelta2 TCR play important roles in immune responses to microbial pathogens by monitoring prenyl pyrophosphate isoprenoid metabolites. Most adult Vgamma2Vdelta2 cells are memory cytotoxic cells that produce IFN-gamma. Recently, murine gammadelta T cells were found to be major sources of IL-17A in antimicrobial and autoimmune responses. To determine if primate gammadelta T cells play similar roles, we characterized IL-17A and IL-22 production by Vgamma2Vdelta2 cells. IL-17A-producing memory Vgamma2Vdelta2 cells exist at low but significant frequencies in adult humans (1:2762 T cells) and at even higher frequencies in adult rhesus macaques. Higher levels of Vgamma2Vdelta2 cells produce IL-22 (1:1864 T cells), although few produce both IL-17A and IL-22. Unlike adult humans, in whom many IL-17A+ Vgamma2Vdelta2 cells also produce IFN-gamma (Tgammadelta1/17), the majority of adult macaques IL-17A+ Vdelta2 cells (Tgammadelta17) do not produce IFN-gamma. To define the cytokine requirements for Tgammadelta17 cells, we stimulated human neonatal Vgamma2Vdelta2 cells with the bacterial Ag, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate, and various cytokines and mAbs in vitro. We find that IL-6, IL-1beta, and TGF-beta are required to generate Tgammadelta17 cells in neonates, whereas Tgammadelta1/17 cells additionally required IL-23. In adults, memory Tgammadelta1/17 and Tgammadelta17 cells required IL-23, IL-1beta, and TGF-beta, but not IL-6. IL-22-producing cells showed similar requirements. Both neonatal and adult IL-17A+ Vgamma2Vdelta2 cells expressed elevated levels of retinoid-related orphan receptor gammat. Our data suggest that, like Th17 alphabeta T cells, Vgamma2Vdelta2 T cells can be polarized into Tgammadelta17 and Tgammadelta1/17 populations with distinct cytokine requirements for their initial polarization and later maintenance.