CD4 T cells play important roles in maintaining IL-17-producing γδ T cell subsets in naïve animals

A proportional balance between αβ and γδ T cell subsets in the periphery is exceedingly well maintained via a homeostatic mechanism. However, a cellular mechanism underlying the regulation remains undefined. We recently reported that a subset of developing γδ T cells spontaneously acquire IL-17-producing capacity even within naïve animals via a TGFβ1-dependent mechanism, thus considered ‘einnate’ IL-17-producing cells. Here we report that γδ T cells generated within αβ T cell (or CD4 T cell)-deficient environments displayed altered cytokine profiles; particularly, ‘einnate’ IL-17 expression was significantly impaired compared to those in wild type mice. Impaired IL-17 production in γδ T cells was directly related to the CD4 T cell deficiency, because depletion of CD4 T cells in wild type mice diminished and adoptive CD4 T cell transfer into TCRβ−/− mice restored IL-17 expression in γδ T cells. CD4 T cell-mediated IL-17 expression required TGFβ1. Moreover, Th17 but not Th1 or Th2 effector CD4 T cells were highly efficient in enhancing γδ T cell IL-17 expression. Taken together, our results highlight a novel CD4 T cell-dependent mechanism that shapes the generation of IL-17+ γδ T cells in naïve settings.