Essential autocrine regulation by IL-21 in the generation of inflammatory T cells

After activation, CD4(+) helper T (T-H) cells differentiate into distinct effector subsets that are characterized by their unique cytokine expression and immunoregulatory function(1,2). During this differentiation, T(H)1 and T(H)2 cells produce interferon-gamma and interleukin (IL)-4, respectively, as autocrine factors necessary for selective lineage commitment. A distinct T-H subset, termed THIL-17, T(H)17 or inflammatory T-H (T(H)i), has been recently identified as a distinct T-H lineage mediating tissue inflammation(3,4). T(H)17 differentiation is initiated by transforming growth factor-beta and IL-6 (refs 5 - 7) and reinforced by IL-23 ( ref. 8), in which signal transduction and activators of transcription ( STAT) 3 and retinoic acid receptor-related orphan receptor (ROR)-gamma mediate the lineage specification(8-10). T(H)17 cells produce IL-17, IL-17F and IL-22, all of which regulate inflammatory responses by tissue cells but have no importance in T(H)17 differentiation(11-14). Here we show that IL-21 is another cytokine highly expressed by mouse T(H)17 cells. IL-21 is induced by IL-6 in activated T cells, a process that is dependent on STAT3 but not ROR-gamma. IL-21 potently induces T(H)17 differentiation and suppresses Foxp3 expression, which requires STAT3 and ROR-gamma, which is encoded by Rorc. IL-21 deficiency impairs the generation of T(H)17 cells and results in protection against experimental autoimmune encephalomyelitis. IL-21 is therefore an autocrine cytokine that is sufficient and necessary for T(H)17 differentiation, and serves as a target for treating inflammatory diseases.