Essential autocrine regulation by IL-21 in the generation of inflammatory T cells (original) (raw)
- Letter
- Published: 20 June 2007
- Xuexian O. Yang1,
- Gustavo Martinez1,
- Yongliang Zhang1,
- Athanasia D. Panopoulos1,
- Li Ma2,
- Kimberly Schluns1,
- Qiang Tian2,
- Stephanie S. Watowich1,
- Anton M. Jetten3 &
- …
- Chen Dong1
Nature volume 448, pages 480–483 (2007)Cite this article
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Abstract
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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References
- Dong, C. & Flavell, R. A. Cell fate decision: T-helper 1 and 2 subsets in immune responses. Arthritis Res. 2, 179–188 (2000)
Article CAS Google Scholar - Glimcher, L. H. & Murphy, K. M. Lineage commitment in the immune system: the T helper lymphocyte grows up. Genes Dev. 14, 1693–1711 (2000)
CAS PubMed Google Scholar - Dong, C. Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells. Nature Rev. Immunol. 6, 329–334 (2006)
Article CAS Google Scholar - Weaver, C. T., Harrington, L. E., Mangan, P. R., Gavrieli, M. & Murphy, K. M. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24, 677–688 (2006)
Article CAS Google Scholar - Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006)
Article ADS CAS Google Scholar - Mangan, P. R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006)
Article ADS CAS Google Scholar - Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006)
Article CAS Google Scholar - Yang, X. O. et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J. Biol. Chem. 282, 9358–9363 (2007)
Article CAS Google Scholar - Chen, Z. et al. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc. Natl Acad. Sci. USA 103, 8137–8142 (2006)
Article ADS CAS Google Scholar - Ivanov, I. I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006)
Article CAS Google Scholar - Chung, Y. et al. Expression and regulation of IL-22 in the IL-17-producing CD4+ T lymphocytes. Cell Res. 16, 902–907 (2006)
Article CAS Google Scholar - Langrish, C. L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005)
Article CAS Google Scholar - Liang, S. C. et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203, 2271–2279 (2006)
Article CAS Google Scholar - Zheng, Y. et al. Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445, 648–651 (2007)
Article CAS Google Scholar - Leonard, W. J. & Spolski, R. Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation. Nature Rev. Immunol. 5, 688–698 (2005)
Article CAS Google Scholar - Wurster, A. L. et al. Interleukin 21 is a T helper (Th) cell 2 cytokine that specifically inhibits the differentiation of naive Th cells into interferon γ-producing Th1 cells. J. Exp. Med. 196, 969–977 (2002)
Article CAS Google Scholar - Suto, A., Wurster, A. L., Reiner, S. L. & Grusby, M. J. IL-21 inhibits IFN-γ production in developing Th1 cells through the repression of Eomesodermin expression. J. Immunol. 177, 3721–3727 (2006)
Article CAS Google Scholar - Akimzhanov, A. M., Yang, X. O. & Dong, C. Chromatin remodeling of interleukin-17 (IL-17)–IL-17F cytokine gene locus during inflammatory helper T cell differentiation. J. Biol. Chem. 282, 5969–5972 (2007)
Article CAS Google Scholar - Okuda, Y. et al. IL-6 plays a crucial role in the induction phase of myelin oligodendrocyte glucoprotein 35–55 induced experimental autoimmune encephalomyelitis. J. Neuroimmunol. 101, 188–196 (1999)
Article CAS Google Scholar - Okuda, Y., Sakoda, S., Saeki, Y., Kishimoto, T. & Yanagihara, T. Enhancement of Th2 response in IL-6-deficient mice immunized with myelin oligodendrocyte glycoprotein. J. Neuroimmunol. 105, 120–123 (2000)
Article CAS Google Scholar - Kurebayashi, S. et al. Retinoid-related orphan receptor γ (RORγ) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis. Proc. Natl Acad. Sci. USA 97, 10132–10137 (2000)
Article ADS CAS Google Scholar - Afkarian, M. et al. T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells. Nature Immunol. 3, 549–557 (2002)
Article CAS Google Scholar - Ozaki, K. et al. A critical role for IL-21 in regulating immunoglobulin production. Science 298, 1630–1634 (2002)
Article ADS CAS Google Scholar - Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nature Immunol. 6, 1133–1141 (2005)
Article CAS Google Scholar - Hjelmstrom, P., Juedes, A. E., Fjell, J. & Ruddle, N. H. B-cell-deficient mice develop experimental allergic encephalomyelitis with demyelination after myelin oligodendrocyte glycoprotein sensitization. J. Immunol. 161, 4480–4483 (1998)
CAS PubMed Google Scholar - Angkasekwinai, P. et al. IL-25 promotes the initiation of pro-allergic type 2 responses. J. Exp. Med. (in the press)
- Kleinschek, M. A. et al. IL-25 regulates Th17 function in autoimmune inflammation. J. Exp. Med. 204, 161–170 (2007)
Article CAS Google Scholar - Laky, K., Lefrancois, L. & Puddington, L. Age-dependent intestinal lymphoproliferative disorder due to stem cell factor receptor deficiency: parameters in small and large intestine. J. Immunol. 158, 1417–1427 (1997)
CAS PubMed Google Scholar
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.
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.
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Authors and Affiliations
- Department of Immunology, M. D. Anderson Cancer Center, Houston, Texas 77030, USA,
Roza Nurieva, Xuexian O. Yang, Gustavo Martinez, Yongliang Zhang, Athanasia D. Panopoulos, Kimberly Schluns, Stephanie S. Watowich & Chen Dong - Institute for Systems Biology, Seattle, Washington 98103, USA,
Li Ma & Qiang Tian - Cell Biology Section, LRB, National Institutes of Health, NIEHS, Research Triangle Park, North Carolina 27709, USA,
Anton M. Jetten
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Correspondence toRoza Nurieva or Chen Dong.
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Supplementary Information
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-γ 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-γ 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. (PDF 319 kb)
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Nurieva, R., Yang, X., Martinez, G. et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells.Nature 448, 480–483 (2007). https://doi.org/10.1038/nature05969
- Received: 07 March 2007
- Accepted: 04 June 2007
- Published: 20 June 2007
- Issue Date: 26 July 2007
- DOI: https://doi.org/10.1038/nature05969