IL-23 drives pathogenic IL-17-producing CD8+ T cells.

IL-17-producing CD8(+) T cells (Tc17) appear to play a role in a range of conditions, such as autoimmunity and cancer. Thus far, Tc17 cells have been only marginally studied, resulting in a paucity of data on their biology and function. We demonstrate that Tc17 and Th17 cells share similar developmental characteristics, including the previously unknown promoting effect of IL-21 on Tc17 cell differentiation and IL-23-dependent expression of IL-22. Both STAT1 and STAT4 are required for optimal development of Tc17 cells and maximal secretion of cytokines. Tc17 cells are cytotoxic, and they can be either pathogenic or nonpathogenic upon adoptive transfer in the model of autoimmune diabetes. Tc17 cells treated with TGF-beta1 plus IL-6 are not diabetogenic, whereas IL-23-treated cells potently induce the disease. IL-17A and IL-17F are necessary but not sufficient for diabetes induction by Tc17 cells. Tc17 cells treated with TGF-beta1 plus IL-6 or IL-23 likely differ in pathogenicity due to their disparate capacity to attract other immune cells and initiate inflammation.