Differential Responsiveness of Innate-like IL-17-and IFN-β-Producing γδ T Cells to Homeostatic Cytokines

gamma delta T cells respond to molecules upregulated following infection or cellular stress using both TCR and non-TCR molecules. The importance of innate signals versus TCR ligation varies greatly. Both innate-like IL-17-producing gamma delta T (gamma delta T-17) and IFN-gamma-producing gamma delta T (gamma delta T-IFN gamma) subsets tune the sensitivity of their TCR following thymic development, allowing robust responses to inflammatory cytokines in the periphery. The remaining conventional gamma delta T cells retain high TCR responsiveness. We determined homeostatic mechanisms that govern these various subsets in the peripheral lymphoid tissues. We found that, although innate-like gamma delta T-17 and gamma delta T-IFN gamma cells share elements of thymic development, they diverge when it comes to homeostasis. Both exhibit acute sensitivity to cytokines compared with conventional gamma delta T cells, but they do not monopolize the same cytokine. gamma delta T-17 cells rely exclusively on IL-7 for turnover and survival, aligning them with NKT17 cells; IL-7 ligation triggers proliferation, as well as promotes survival, upregulating Bcl-2 and Bcl-x(L). gamma delta T-IFN gamma cells instead depend heavily on IL-15. They display traits analogous to memory CD8(+) T cells and upregulate Bcl-x(L) and Mcl-1 upon cytokine stimulation. The conventional gamma delta T cells display low sensitivity to cytokine-alone stimulation and favor IL-7 for their turnover, characteristics reminiscent of naive alpha beta T cells, suggesting that they may also require tonic TCR signaling for population maintenance. These survival constraints suggest that gamma delta T cell subsets do not directly compete with each other for cytokines, but instead fall into resource niches with other functionally similar lymphocytes.