Abstract
Although the role of the TH1 and TH17 subsets of helper T cells as disease mediators in autoimmune neuroinflammation remains a subject of some debate, none of their signature cytokines are essential for disease development. Here we report that interleukin 23 (IL-23) and the transcription factor RORγt drove expression of the cytokine GM-CSF in helper T cells, whereas IL-12, interferon-γ (IFN-γ) and IL-27 acted as negative regulators. Autoreactive helper T cells specifically lacking GM-CSF failed to initiate neuroinflammation despite expression of IL-17A or IFN-γ, whereas GM-CSF secretion by Ifng−/−Il17a−/− helper T cells was sufficient to induce experimental autoimmune encephalomyelitis (EAE). During the disease effector phase, GM-CSF sustained neuroinflammation via myeloid cells that infiltrated the central nervous system. Thus, in contrast to all other known helper T cell–derived cytokines, GM-CSF serves a nonredundant function in the initiation of autoimmune inflammation regardless of helper T cell polarization.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Gutcher, I. & Becher, B. APC-derived cytokines and T cell polarization in autoimmune inflammation. J. Clin. Invest. 117, 1119–1127 (2007).
Chu, C.Q., Wittmer, S. & Dalton, D.K. Failure to suppress the expansion of the activated CD4 T cell population in interferon γ-deficient mice leads to exacerbation of experimental autoimmune encephalomyelitis. J. Exp. Med. 192, 123–128 (2000).
Becher, B., Durell, B.G. & Noelle, R.J. Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J. Clin. Invest. 110, 493–497 (2002).
Gran, B. et al. IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination. J. Immunol. 169, 7104–7110 (2002).
Cua, D.J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003).
Kreymborg, K., Bohlmann, U. & Becher, B. IL-23: changing the verdict on IL-12 function in inflammation and autoimmunity. Expert Opin. Ther. Targets 9, 1123–1136 (2005).
Oppmann, B. et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13, 715–725 (2000).
Aggarwal, S., Ghilardi, N., Xie, M.H., de Sauvage, F.J. & Gurney, A.L. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J. Biol. Chem. 278, 1910–1914 (2003).
Littman, D.R. & Rudensky, A.Y. Th17 and regulatory T cells in mediating and restraining inflammation. Cell 140, 845–858 (2010).
Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133–1141 (2005).
Kreymborg, K. et al. IL-22 is expressed by Th17 cells in an IL-23-dependent fashion, but not required for the development of autoimmune encephalomyelitis. J. Immunol. 179, 8098–8104 (2007).
Hofstetter, H.H. et al. Therapeutic efficacy of IL-17 neutralization in murine experimental autoimmune encephalomyelitis. Cell. Immunol. 237, 123–130 (2005).
Haak, S. et al. IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice. J. Clin. Invest. 119, 61–69 (2009).
McGeachy, M.J. et al. TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell-mediated pathology. Nat. Immunol. 8, 1390–1397 (2007).
Sonderegger, I., Kisielow, J., Meier, R., King, C. & Kopf, M. IL-21 and IL-21R are not required for development of Th17 cells and autoimmunity in vivo. Eur. J. Immunol. 38, 1833–1838 (2008).
Langrish, C.L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005).
Kroenke, M.A., Carlson, T.J., Andjelkovic, A.V. & Segal, B.M. IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition. J. Exp. Med. 205, 1535–1541 (2008).
McGeachy, M.J. et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat. Immunol. 10, 314–324 (2009).
Gyulveszi, G., Haak, S. & Becher, B. IL-23-driven encephalo-tropism and Th17 polarization during CNS-inflammation in vivo. Eur. J. Immunol. 39, 1864–1869 (2009).
McQualter, J.L. et al. Granulocyte macrophage colony-stimulating factor: a new putative therapeutic target in multiple sclerosis. J. Exp. Med. 194, 873–882 (2001).
Ponomarev, E.D. et al. GM-CSF production by autoreactive T cells is required for the activation of microglial cells and the onset of experimental autoimmune encephalomyelitis. J. Immunol. 178, 39–48 (2007).
Kroenke, M.A., Chensue, S.W. & Segal, B.M. EAE mediated by a non-IFN-γ/non-IL-17 pathway. Eur. J. Immunol. 40, 2340–2348 (2010).
Harrington, L.E. et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6, 1123–1132 (2005).
Wensky, A.K. et al. IFN-γ determines distinct clinical outcomes in autoimmune encephalomyelitis. J. Immunol. 174, 1416–1423 (2005).
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).
Bettelli, E. et al. Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. J. Exp. Med. 200, 79–87 (2004).
Lugo-Villarino, G., Maldonado-Lopez, R., Possemato, R., Penaranda, C. & Glimcher, L.H. T-bet is required for optimal production of IFN-γ and antigen-specific T cell activation by dendritic cells. Proc. Natl. Acad. Sci. USA 100, 7749–7754 (2003).
Medvedev, A., Yan, Z.H., Hirose, T., Giguere, V. & Jetten, A.M. Cloning of a cDNA encoding the murine orphan receptor RZR/RORγ and characterization of its response element. Gene 181, 199–206 (1996).
Diveu, C. et al. IL-27 blocks RORc expression to inhibit lineage commitment of Th17 cells. J. Immunol. 182, 5748–5756 (2009).
Fitzgerald, D.C. et al. Suppressive effect of IL-27 on encephalitogenic Th17 cells and the effector phase of experimental autoimmune encephalomyelitis. J. Immunol. 179, 3268–3275 (2007).
Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).
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).
Korn, T. et al. IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature 448, 484–487 (2007).
Ghoreschi, K. et al. Generation of pathogenic TH17 cells in the absence of TGF-β signalling. Nature 467, 967–971 (2010).
Stanley, E. et al. Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc. Natl. Acad. Sci. USA 91, 5592–5596 (1994).
Sonderegger, I. et al. GM-CSF mediates autoimmunity by enhancing IL-6-dependent Th17 cell development and survival. J. Exp. Med. 205, 2281–2294 (2008).
Campbell, I.K. et al. Protection from collagen-induced arthritis in granulocyte-macrophage colony-stimulating factor-deficient mice. J. Immunol. 161, 3639–3644 (1998).
King, I.L., Dickendesher, T.L. & Segal, B.M. Circulating Ly-6C+ myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease. Blood 113, 3190–3197 (2009).
Greter, M. et al. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat. Med. 11, 328–334 (2005).
Becher, B., Durell, B.G. & Noelle, R.J. IL-23 produced by CNS-resident cells controls T cell encephalitogenicity during the effector phase of experimental autoimmune encephalomyelitis. J. Clin. Invest. 112, 1186–1191 (2003).
Stromnes, I.M. & Goverman, J.M. Passive induction of experimental allergic encephalomyelitis. Nat. Protoc. 1, 1952–1960 (2006).
Streeck, H. et al. Rapid ex vivo isolation and long-term culture of human Th17 cells. J. Immunol. Methods 333, 115–125 (2008).
Acknowledgements
We thank A. Waisman, S. Haak, M. Dreano and and M. Greter for critical review of the manuscript; I. Ivanov and D. Littman (New York University School of Medicine) for the plasmid RORγt-IRES-GFP; V. Kuchroo (Harvard University) for 2D2 mice; and Y. Iwakura (University of Tokyo) for Il17a−/− mice. Supported by the Swiss National Science Foundation (31003AB.131091 to B.B.), the Swiss Multiple Sclerosis Society (B.B. and T.S.), the Koetser Foundation (B.B.), Merck-Serono-Geneva (B.B.), Forschungskredit of the University of Zurich (L.C.) and Gemeinnützige Hertie–Stiftung (A.F.).
Author information
Authors and Affiliations
Contributions
B.B., L.C. and G.G. designed experiments, analyzed data and wrote the paper; L.C. and G.G. did the experiments; V.T. helped do the experiments; L.H., T.S. and A.F. designed, did and analyzed the experiments with the chimeric Csf2rb−/− mice; L.M. generated neutralizing chimeric monoclonal antibody to GM-CSF; and B.B. supervised the study.
Corresponding author
Ethics declarations
Competing interests
L.M. is employed by Merck Serono S.A, which is involved in the discovery and commercialization of therapeutics for the prevention and treatment of human diseases.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–4 and Supplementary Methods (PDF 1026 kb)
Rights and permissions
About this article
Cite this article
Codarri, L., Gyülvészi, G., Tosevski, V. et al. RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol 12, 560–567 (2011). https://doi.org/10.1038/ni.2027
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ni.2027
This article is cited by
-
Mechanisms and functions of SUMOylation in health and disease: a review focusing on immune cells
Journal of Biomedical Science (2024)
-
Shaping immune landscape of colorectal cancer by cholesterol metabolites
EMBO Molecular Medicine (2024)
-
Gut microbial metabolite deoxycholic acid facilitates Th17 differentiation through modulating cholesterol biosynthesis and participates in high-fat diet-associated colonic inflammation
Cell & Bioscience (2023)
-
SENP2 restrains the generation of pathogenic Th17 cells in mouse models of colitis
Communications Biology (2023)
-
TH17 cell heterogeneity and its role in tissue inflammation
Nature Immunology (2023)