Cytokine Requirements for the Differentiation and Expansion of IL-17A-and IL-22-Producing Human Vγ2Vδ2 T Cells

Human gamma delta T cells expressing the V gamma 2V delta 2 TCR play important roles in immune responses to microbial pathogens by monitoring prenyl pyrophosphate isoprenoid metabolites. Most adult V gamma 2V delta 2 cells are memory cytotoxic cells that produce IFN-gamma. Recently, murine gamma delta T cells were found to be major sources of IL-17A in antimicrobial and autoimmune responses. To determine if primate gamma delta T cells play similar roles, we characterized IL-17A and IL-22 production by V gamma 2V delta 2 cells. IL-17A-producing memory V gamma 2V delta 2 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 V gamma 2V delta 2 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(+) V gamma 2V delta 2 cells also produce IFN-gamma (T gamma delta 1/17), the majority of adult macaques IL-17A(+)V delta 2 cells (T gamma delta 17) do not produce IFN-gamma. To define the cytokine requirements for T gamma delta 17 cells, we stimulated human neonatal V gamma 2V delta 2 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-1 beta, and TGF-beta are required to generate T gamma delta 17 cells in neonates, whereas T gamma delta 1/17 cells additionally required IL-23. In adults, memory T gamma beta 1/17 and T gamma delta 17 cells required IL-23, IL-1 beta, and TGF-beta, but not IL-6. IL-22-producing cells showed similar requirements. Both neonatal and adult IL-17A(+) V gamma 2V delta 2 cells expressed elevated levels of retinoid-related orphan receptor gamma t. Our data suggest that, like Th17 alpha beta T cells, V gamma 2V delta 2 T cells can be polarized into T gamma delta 17 and T gamma delta 1/17 populations with distinct cytokine requirements for their initial polarization and later maintenance. The Journal of Immunology, 2010, 184: 7268-7280.