CD4 T cells play important roles in maintaining IL‐17‐producing γδ T‐cell subsets in naive animals

A proportional balance between αβ and γδ T‐cell subsets in the periphery is exceedingly well maintained by a homeostatic mechanism. However, a cellular mechanism underlying the regulation remains undefined. We recently reported that a subset of developing γδ T cells spontaneously acquires interleukin (IL)‐17‐producing capacity even within naive animals through a transforming growth factor (TGF)β1‐dependent mechanism, thus considered ‘innate’ 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, ‘innate’ IL‐17 expression was significantly impaired compared with those in wild‐type mice. Impaired IL‐17 production in γδ T cells was directly related to CD4 T‐cell deficiency, because depletion of CD4 T cells in wild‐type mice diminished and adoptive CD4 T‐cell transfer into T‐cell receptor β−/− 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 naive settings.