title: Essential autocrine regulation by IL-21 in the generation of inflammatory T cells.
abstract: After activation, CD4+ helper T (T(H)) cells differentiate into distinct effector subsets that are characterized by their unique cytokine expression and immunoregulatory function. 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 T(HIL-17), T(H)17 or inflammatory T(H) (T(H)i), has been recently identified as a distinct T(H) lineage mediating tissue inflammation. 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. 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. 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.
authors.affiliation: Department of Immunology, M. D. Anderson Cancer Center, Houston, Texas 77030, USA. rnurieva@mdanderson.org
authors.forename: Roza
authors.initials: R
authors.lastname: Nurieva
authors.forename: Xuexian O
authors.initials: XO
authors.lastname: Yang
authors.forename: Gustavo
authors.initials: G
authors.lastname: Martinez
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Athanasia D
authors.initials: AD
authors.lastname: Panopoulos
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.forename: Kimberly
authors.initials: K
authors.lastname: Schluns
authors.forename: Qiang
authors.initials: Q
authors.lastname: Tian
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Watowich
authors.forename: Anton M
authors.initials: AM
authors.lastname: Jetten
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D002454:Cell Differentiation; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007378:Interleukins / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D000098546:Interleukin-21
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D015850:Interleukin-6; D007378:Interleukins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; C539901:Rorc protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D000098546:Interleukin-21