Cited by 1,191Multiple Sclerosis Research StudiesPsoriasis: Treatment and PathogenesisT-cell and B-cell Immunology

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RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation

Codarri, Laura, Gyülvészi, Gabor, Tosevski, Vinko, Hesske, Lysann, Fontana, Adriano, Magnenat, Laurent, Suter, Tobias, Becher, Burkhard·2011·Nature Immunology

DOI 10.1038/ni.2027

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Abstract

Although the role of the T(H)1 and T(H)17 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.

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Discovery of the First-in-Class RORγ Covalent Inhibitors for Treatment of Castration-Resistant Prostate Cancer
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Background
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Two- and three-color STORM analysis reveals higher-order assembly of leukotriene synthetic complexes on the nuclear envelope of murine neutrophils
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Th17 Cells in Autoimmune Inflammation and Demyelination in the Central Nervous System
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Ca2+ Signaling Augmented by ORAI1 Trafficking Regulates the Pathogenic State of Effector T Cells
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An analysis of single-cell data reveals therapeutic effects of AMG487 in experimental autoimmune uveitis
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Insights into Gene Expression of Activated Pathogenic Autoimmune T Cells - Studies in Experimental Multiple Sclerosis-like Model
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“Moreover, GM-CSF and IL-3 were recently shown to drive the activation of autoreactive T cells [32,33].”
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Cellular Immunity and Multiple Sclerosis: Current Understanding
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“Data from the experimental autoimmune encephalomyelitis (EAE) animal models of MS show that myelin-specific T cells promote disease pathology by releasing proinflammatory cytokines, such as IL-17, IFN-γ , TNF, and GM-CSF, which trigger demyelination and axonal transection [18,19].”
BackgroundMethod
Discovery and pharmacological characterization of 1,2,3,4-tetrahydroquinoline derivatives as RORγ inverse agonists against prostate cancer
Wu, X., Luo, X., Li, C.-C., Zhao, X., Zhang, C., Chen, X., Lu, Z.-F., Wu, T., Yu, H.-N., Peng, C., et al. (2024) · Acta Pharmacologica Sinica · doi:10.1038/s41401-024-01274-z · Cited by 3
Regulatory T cells suppress GM-CSF-producing T helper cells via IL-2 modulation to restrain immunopathology
Costa-Pereira, S., Lanzinger, M., Andreadou, M., Nuñez, N., Villar-Vesga, J., Prisco, F., Häne, P., Roussel, E., Krishnarajah, S., Lindemann, R. C., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115642 · Cited by 3
Vitamin D and exercise in obesity: a neurovascular–muscle axis
Zheng, X., & Zhang, C. (2026) · Frontiers in Nutrition · doi:10.3389/fnut.2026.1750915 · Cited by 3
Development of Central Nervous System Autoimmunity Is Impaired in the Absence of Wiskott-Aldrich Syndrome Protein
Bosticardo, M., Musio, S., Fontana, E., Angiari, S., Draghici, E., Constantin, G., Poliani, P. L., Pedotti, R., & VILLA, A. M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0086942 · Cited by 3
“GM-CSF, recently shown to play an essential function in the initiation of autoimmune neuroinflammation in EAE [25], and IL-2 were also increased in splenocytes of Was mice upon antigen stimulation as Impaired CNS Autoimmunity in the Absence of WASP”
Background
Serotonergic system as a therapeutic target in multiple sclerosis
Sviridova, A. A., Melnikov, M., Belousova, O., Rogovskii, V., Pashenkov, M. V., & Boyko, A. N. (2019) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro20191192264 · Cited by 2
Comprehensive Analysis of the Immune and Stromal Compartments of the CNS in EAE Mice Reveal Pathways by Which Chloroquine Suppresses Neuroinflammation
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TPN10475 Constrains Effector T Lymphocytes Activation and Attenuates Experimental Autoimmune Encephalomyelitis Pathogenesis by Facilitating TGF-β Signal Transduction
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“The results showed that, consistent with the proportion of CD4 + T subpopulations in spleen, the levels of IFN-γ and TNF-α secreted by Th1 cells were significantly decreased by TPN10475 in the supernatant after re-stimulation, while the levels of IL-17 A and GM-CSF, characteristic cytokines of Th17 cells, also decreas…”
Influential
In silico design of RORγ inverse agonists based on 3D-QSAR and molecular docking
Deng, R., He, W., Guo, H., Su, Z., Wu, W., & Wu, Z. (2022) · New Journal of Chemistry · doi:10.1039/d1nj05185g · Cited by 3
Th1-, Th17- und Th1+17-Zellen
Chang, H., Kamradt, T., & Schulze‐Koops, H. (2011) · Zeitschrift für Rheumatologie · doi:10.1007/s00393-011-0779-5 · Cited by 3
Expression and role of granulocyte macrophage colony-stimulating factor receptor (GM-CSFR) and granulocyte colony-stimulating factor receptor (G-CSFR) on Ph-positive acute B lymphoblastic leukemia
Tan, M., Chen, M., Chen, Y.-Z., & Wu, Y. (2018) · Hematology · doi:10.1080/10245332.2018.1426540 · Cited by 3
DIRECT EFFECTS OF GM-CSF ON THE FUNCTIONS OF HUMAN MONOCYTES/MACROPHAGES
Gazatova, N., Meniailo, M. E., Malashchenko, V., Goncharov, A., Melashchenko, O., Morozova, E. M., & Seledtsov, V. (2019) · Medical Immunology · doi:10.15789/1563-0625-2019-3-419-426 · Cited by 3
“В частности, GM-CSF способен поддерживать дифференцировку и выживаемость дендритных клеток, запускающих антигензависимую пролиферацию и дифференцировку Т-лимфоцитов [14, 17] и регулирующих иммунные реакции на всем их протяжении [4, 7].”
A TLR5 mono-agonist restores inhibited immune responses to Streptococcus pneumoniae during influenza virus infection in human monocytes
Maguire, P. T., Loughran, S. T., Harvey, R., & JOHNSON, P. A. (2021) · PLoS ONE · doi:10.1371/journal.pone.0258261 · Cited by 3
“RORC is a transcription factor specific to the Th17 response, which plays an important role in the upregulation of IL-23 expression [17,18,20,46,47].”
Background
Cytokines
O’Shea, J. J., Gadina, M., Siegel, R. M., & Farber, J. M. (2015) · Elsevier eBooks · doi:10.1016/b978-0-323-09138-1.00013-9 · Cited by 4
Multiple Sclerosis
Wesley, S., & Hafler, D. A. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-812102-3.00051-8 · Cited by 4
GM-CSF Promotes the Survival of Peripheral-Derived Myeloid Cells in the Central Nervous System for Pain-Induced Relapse of Neuroinflammation
Matsuyama, S., Yamamoto, R., Murakami, K., Takahashi, N., Nishi, R., Ishii, A., Nio‐Kobayashi, J., Abe, N., Tanaka, K., Jiang, J., et al. (2023) · The Journal of Immunology · doi:10.4049/jimmunol.2200567 · Cited by 4
Macrophage/Microglia Plasticity in Multiple Sclerosis
Vogel, D. Y. S. (2015) · Pure Amsterdam UMC · Cited by 3
The Immunobiology of Asthma
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RORα enforces stability of the T-helper-17 cell effector programPreprint
Lee, J.-Y., Hall, J., Pokrovskii, M., Kroehling, L., Wu, L., & Littman, D. (2020) · bioRxiv · doi:10.1101/2020.12.15.422921 · Cited by 3
“(B and C) Normalized counts of autoimmune disease-associated (Il1r1, Il23r, Bhlhe40), pathogenic (Csf2) genes (B) and Rorc (C) in TWT and TAKO Il17aeGFP+ Th17 cells from the DLN (TWT (n = 3) and TAKO (n = 3)) and SC (TWT (n = 3) and TAKO (n = 2)) at peak of EAE.”
BackgroundInfluential
Chemokine positioning determines mutually exclusive roles for their receptors in extravasation of pathogenic human T cellsPreprint
Parween, F., Singh, S. P., Zhang, H. H., Kathuria, N., Otaizo-Carrasquero, F. A., Shamsaddini, A., Gardina, P. J., Ganesan, S., Kabát, J., Lorenzi, H., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.01.25.525561 · Cited by 3
“The critical effector cytokines that have been shown to mediate the pathogenic activity of these cells have included GM-CSF 38, 48, 51, 52, 53, 54, 55, 56, 57, 58 , IFN- 36, 52 and IL-17 55 .”
Regulatory T-cells in multiple sclerosis produce IL-10 in the central 1 nervous system but are activated by Epstein-Barr VirusPreprint
Pulvirenti, N., Righetti, C., Clemente, F., Serafini, B., Cordiglieri, C., Vasco, C., Maioli, S., Pietroboni, A. M., Galeota, E., Rosicarelli, B., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.30.605745 · Cited by 3
The multiple roles of GM-CSF in autoimmune and autoinflammatory uveitis
Tao, T., Jiang, G., Su, Y., He, D., Zhu, L., Jiang, Q., & Su, W. (2025) · Biochemical Pharmacology · doi:10.1016/j.bcp.2025.117090 · Cited by 3

Authors: Codarri, L., Gyülvészi, G., Tosevski, V., Hesske, L., Fontana, A., Magnenat, L., Suter, T., & Becher, B.
Affiliations: University Hospital Zurich (CH)
University of Zurich (CH)
Merck Serono S.A. (Switzerland) (CH)
Corresponding author: Becher, Burkhard
ORCID: Magnenat, Laurent
Suter, Tobias
Becher, Burkhard
Venue: Nature Immunology
Publisher: Springer Science and Business Media LLC
Published: 2011-04-24
Volume: 12
Issue: 6
Pages: 560-567
ISSN: 1529-2908 (ISSN-L)
1529-2916
DOI: 10.1038/ni.2027
OpenAlex: W2157837362
Cited by: 1,191
References: 44
Citations by year: 2026: 31 · 2025: 48 · 2024: 60 · 2023: 53 · 2022: 61 · 2021: 73 · 2020: 85 · 2019: 83 · 2018: 72 · 2017: 99 · 2016: 96 · 2015: 117 · 2014: 103 · 2013: 98 · 2012: 82
FWCI: 70.23
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Immunology (publishedVersion)
PubMed (publishedVersion)
Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
Topics: Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords: RORγt, GM-CSF, experimental autoimmune encephalomyelitis, T helper cells, IL-23, autoimmune neuroinflammation, Th1 cells, Th17 cells, myeloid cell infiltration, IL-12, interferon-gamma, IL-27, cytokine regulation
MeSH terms: Animals, Cells, Cultured, Encephalomyelitis, Autoimmune, Experimental, Female, Flow Cytometry, Glycoproteins, T-Lymphocytes, Helper-Inducer, Interferon-gamma, Interleukins, Male, Mice, Inbred C57BL, Mice, Inbred Strains, Mice, Transgenic, Peptide Fragments, Granulocyte-Macrophage Colony-Stimulating Factor, Mice, Knockout, Th1 Cells, Interleukin-12, Interleukin-17, Mice, Interleukin-23, Nuclear Receptor Subfamily 1, Group F, Member 3, Th17 Cells, Myelin-Oligodendrocyte Glycoprotein

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RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation

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