After activation, CD4+ helper T (TH) cells differentiate into distinct effector subsets that are characterized by their unique cytokine expression and immunoregulatory function1,2. During this differentiation, TH1 and TH2 cells produce interferon-γ and interleukin (IL)-4, respectively, as autocrine factors necessary for selective lineage commitment. A distinct TH subset, termed THIL-17, TH17 or inflammatory TH (THi), has been recently identified as a distinct TH lineage mediating tissue inflammation3,4. TH17 differentiation is initiated by transforming growth factor-β 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)-γ mediate the lineage specification8,9,10. TH17 cells produce IL-17, IL-17F and IL-22, all of which regulate inflammatory responses by tissue cells but have no importance in TH17 differentiation11,12,13,14. Here we show that IL-21 is another cytokine highly expressed by mouse TH17 cells. IL-21 is induced by IL-6 in activated T cells, a process that is dependent on STAT3 but not ROR-γ. IL-21 potently induces TH17 differentiation and suppresses Foxp3 expression, which requires STAT3 and ROR-γ, which is encoded by Rorc. IL-21 deficiency impairs the generation of TH17 cells and results in protection against experimental autoimmune encephalomyelitis. IL-21 is therefore an autocrine cytokine that is sufficient and necessary for TH17 differentiation, and serves as a target for treating inflammatory diseases.
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We thank the Dong laboratory members for their help. The work is supported by research grants from NIH (to C.D.), an Intramural Research Program of the NIEHS, NIH (to A.M.J.), and the M. D. Anderson Cancer Center (to S.S.W.). R.N. received a postdoctoral fellowship from the Arthritis Foundation and is a recipient of a Scientist Development Grant from the American Heart Association. K.S. and C.D. are M. D. Anderson Cancer Center Trust Fellows, and C.D. is a Cancer Research Institute Investigator and American Lung Association Career Investigator.
Author Contributions C.D. and R.N. designed the research and analysed the data. R.N., X.O.Y., G.M., Y.Z., A.D.P., L.M. and K.S. performed the experiments, and R.N., Q.T., S.S.W., A.M.J. and C.D. prepared the manuscript.
This file contains Supplementary Figures S1-S8 and Legends. Figure S1 shows that IL-21 protein is highly produced by TH17 cells. Figure S2 shows the requirement of STAT3 and ROR for expression of TH17 cytokines. Figure S3 shows that IL-21 similar to IL-6 regulates TH17 differentiation. Figure S4 shows enhanced Foxp3 expression in STAT3 or ROR deficient TH cells following TH17 differentiation. Figure S5 shows normal development of T and B cells in IL-21 deficient mice. Figure S6 shows that exogenous IL-21 restores TH17 differentiation in IL-21 deficient T cells. Figure S7 shows that IL-21 deficiency impairs IL-17 expression in vivo. Figure 8 shows revised scheme of TH differentiation.
About this article
Scientific Reports (2018)