1. Department of Immunology, M. D. Anderson Cancer Center, Houston, Texas 77030, USA
2. Institute for Systems Biology, Seattle, Washington 98103, USA
3. Cell Biology Section, LRB, National Institutes of Health, NIEHS, Research Triangle Park, North Carolina 27709, USA

Correspondence to: Roza Nurieva¹Chen Dong¹ Correspondence and requests for materials should be addressed to C.D. (Email: cdong@mdanderson.org) or R.N. (Email: rnurieva@mdanderson.org).

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^{1, 2}. During this differentiation, T_H1 and T_H2 cells produce interferon- and interleukin (IL)-4, respectively, as autocrine factors necessary for selective lineage commitment. A distinct T_H subset, termed T_HIL-17, T_H17 or inflammatory T_H (T_Hi), has been recently identified as a distinct T_H lineage mediating tissue inflammation^{3, 4}. T_H17 differentiation is initiated by transforming growth factor- 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)- mediate the lineage specification^{8, 9, 10}. T_H17 cells produce IL-17, IL-17F and IL-22, all of which regulate inflammatory responses by tissue cells but have no importance in T_H17 differentiation^{11, 12, 13, 14}. Here we show that IL-21 is another cytokine highly expressed by mouse T_H17 cells. IL-21 is induced by IL-6 in activated T cells, a process that is dependent on STAT3 but not ROR-. IL-21 potently induces T_H17 differentiation and suppresses Foxp3 expression, which requires STAT3 and ROR-, which is encoded by Rorc. IL-21 deficiency impairs the generation of T_H17 cells and results in protection against experimental autoimmune encephalomyelitis. IL-21 is therefore an autocrine cytokine that is sufficient and necessary for T_H17 differentiation, and serves as a target for treating inflammatory diseases.

1. Department of Immunology, M. D. Anderson Cancer Center, Houston, Texas 77030, USA
2. Institute for Systems Biology, Seattle, Washington 98103, USA
3. Cell Biology Section, LRB, National Institutes of Health, NIEHS, Research Triangle Park, North Carolina 27709, USA

Correspondence to: Roza Nurieva¹Chen Dong¹ Correspondence and requests for materials should be addressed to C.D. (Email: cdong@mdanderson.org) or R.N. (Email: rnurieva@mdanderson.org).

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