IL-21 produced by Tfh cells has been shown to induce differentiation of CD8+ T cells into cytotoxic effector cells by upregulating key molecules such as IFN-γ and granzyme B in anti-tumor immunity or viral infection (37,38), suggesting that Tfh-like Tet2/3 DKO ex-Treg cells induced cytotoxic CD8+ T cell differentiation via IL-21 in Tet2/3 DKO-severe mice. This evidence concerns the gene IFNG and viral infectious disease.