TY - JOUR
T1 - Essential autocrine regulation by IL-21 in the generation of inflammatory T cells
AU - Nurieva, Roza
AU - Yang, Xuexian O.
AU - Martinez, Gustavo
AU - Zhang, Yongliang
AU - Panopoulos, Athanasia D.
AU - Ma, Li
AU - Schluns, Kimberly
AU - Tian, Qiang
AU - Watowich, Stephanie S.
AU - Jetten, Anton M.
AU - Dong, Chen
N1 - Funding Information:
Acknowledgements 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.
PY - 2007/7/26
Y1 - 2007/7/26
N2 - After activation, CD4+ helper T (TH) cells differentiate into distinct effector subsets that are characterized by their unique cytokine expression and immunoregulatory function. 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 (T Hi), has been recently identified as a distinct TH lineage mediating tissue inflammation. 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 specification. 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 differentiation. 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.
AB - After activation, CD4+ helper T (TH) cells differentiate into distinct effector subsets that are characterized by their unique cytokine expression and immunoregulatory function. 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 (T Hi), has been recently identified as a distinct TH lineage mediating tissue inflammation. 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 specification. 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 differentiation. 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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U2 - 10.1038/nature05969
DO - 10.1038/nature05969
M3 - Article
C2 - 17581589
AN - SCOPUS:34547204946
SN - 0028-0836
VL - 448
SP - 480
EP - 483
JO - Nature
JF - Nature
IS - 7152
ER -