The development of IL‐17/IFN‐γ‐double producing CTLs from Tc17 cells is driven by epigenetic suppression of Socs3 gene promoter

The plasticity of T lymphocytes induced by epigenetic modifications of gene promoters may play a pivotal role in controlling their effector functions, which are sometimes causally associated with immune disorders. IL ‐17‐producing T cells, which induce type 17 immune responses, are newly identified pathogenic effector cells. The type 1 signature cytokine IFN‐γ strongly inhibits their differentiation, indicating a mutually exclusive relationship between type 17‐ and type 1‐immune responses. However, many reports indicate the presence of a unique IL‐17/IFN‐γ‐double producing T‐cell subset in various inflammatory settings, although the mechanisms responsible for their development and their precise functions remain unclear. Here, we demonstrate that IL‐12 permits the conversion of mouse IL‐17‐producing CD8+ T (Tc17) cells to IL‐17/IFN‐γ‐double producing CD8+ T (Tc17/IFN‐γ) cells, and that this conversion is due to repressive epigenetic modifications of Socs3 gene promoters. Moreover, we show that SOCS3 strongly regulates the capability of Tc17 cells to produce IL‐17, in addition to regulating the expression of the type 17‐master regulator RORγt. These findings elucidate the mechanisms underlying the conversion of Tc17 cells into Tc17/IFN‐γ cells. As these cells are known to have potent antitumor activities, manipulation of these conversion mechanisms for therapeutic tumor immunity may be possible.