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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Background
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Background
Recurrent late-onset neutropenia following treatment with different B cell-depleting strategies in multiple sclerosis
Protopapa, M., Schraad, M., Pape, K., Steffen, F., Steenken, L., Zipp, F., Fleischer, V., & Bittner, S. (2024) · Med · doi:10.1016/j.medj.2024.10.006 · Cited by 9
Metabolic Stress Expands Polyfunctional, Proinflammatory Th 17 Cells in Patients With Psoriatic Arthritis for Whom There is Interleukin‐23–Independent Interleukin‐17 Production
Stober, C. B., Ellis, L., GOODALL, J. C., Veldhoen, M., & Gaston, H. (2024) · Arthritis & Rheumatology · doi:10.1002/art.43095 · Cited by 11
“We sought to explore the effects of IL-23 and TGF β on IL-17, GM-CSF, and IFN γ production by naive T cells differentiated under Th 17 -polarizing or Th 1 -polarizing conditions, in patients with PsA.”
Influential
Pathways to Progressive Disability in Multiple Sclerosis: The Role of Glial Cells in Chronic CNS Inflammation
Siffrin, V. (2025) · Glia · doi:10.1002/glia.70044 · Cited by 10
“Key factors include the master transcription factor RORγt which drives Th17 cell differentiation (Ivanov et al. 2006), IL-23, which stabilizes Th17 cells, and GMCSF, which mediates the manifestation of clinical signs of EAE (McGeachy et al. 2009; Codarri et al. 2011; El-Behi et al. 2011).”
T cell-macrophage crosstalk in GVHD and cancer immunotherapy
Song, Q., Chaudagar, K. K., Zhang, X., & Waller, E. K. (2025) · Cell investigation. · doi:10.1016/j.clnves.2025.100035 · Cited by 9
IL-18 drives the Bhlhe40-mediated pathogenic Th17 cell response and exacerbates autoimmune disease progression
Tang, Y., Zhao, Y., Chen, Z., Shi, X., Zhou, Y., Li, L., Xiao, F., Zhu, X., Qing, Y., Mo, Y., et al. (2025) · Cellular and Molecular Immunology · doi:10.1038/s41423-025-01356-w · Cited by 13
Exhausted KLRG1hi CD8+ T and pathogenic GZMA+ Th17 cells are associated with the mild Mycoplasma pneumoniae pneumonia in children
Zhan, J.-Y., Luo, R., Li, C., Zhong, L., Wu, Q., Wang, R., Chen, D.-P., Chen, X., Ren, K.-Y., Chen, Z., et al. (2025) · Journal of Infection · doi:10.1016/j.jinf.2025.106642 · Cited by 10
CCL20-CCR6 signaling alters the metabolic reprogramming to promote the pathogenic Th17 cell differentiation
Meitei, H. T., Kulkarni, N., Shirolkar, A. R., Rapole, S., Sharma, P., Mujeeb, V. R., Srivastava, S., & Lal, G. (2025) · iScience · doi:10.1016/j.isci.2025.114385 · Cited by 8
“29,30 Our results showed that CCR6 +/+ CD4 + T cells had a higher frequency of IL-23R + and GM-CSF + expression than CCR6 − / − CD4 + T cells in the GALTs (Figure S1A).”
Inflame and restrain — the paradoxical roles of IL-12 and IL-23 in immunity
Rindlisbacher, L., Navarro, M. N., & Becher, B. (2026) · Nature reviews. Immunology · doi:10.1038/s41577-025-01255-1 · Cited by 18
“Instead, IL-23 induces a broader inflammatory programme, including the production of GM-CSF and other mediators that are necessary for encephalitogenic T cell activity 59,63 .”
Treatment with anti-FcεRIα antibody exacerbates EAE and T-cell immunity against myelin
Musio, S., Costanza, M., Poliani, P. L., Fontana, E., Cominelli, M., Abolafio, G., Steinman, L., & Pedotti, R. (2017) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000000342 · Cited by 9
“Effects of anti-FceRIa treatment on serum concentration of histamine and total IgE. Histamine has been shown to modulate the immune response in EAE,30–32 and histidine decarboxylase–deficient mice (2/2 mice), that are histamine deficient, displayed exacerbated EAE, and increased Th1 responses.25,33 Because basophils,…”
BackgroundInfluential
Single-cell analysis of immune cells on gingiva-derived mesenchymal stem cells in experimental autoimmune uveitis
Gao, Y., Duan, R., Li, H., Jiang, L., Tao, T., Liu, X., Zhu, L., Li, Z., Chen, B., Zheng, S. G., et al. (2023) · iScience · doi:10.1016/j.isci.2023.106729 · Cited by 9
Discovery of novel triazine derivatives as potent retinoic acid receptor-related orphan receptor γt (RORγt) inverse agonists
Lu, L., Chen, S., Yu, M., Zhou, R., Guo, S., Chen, J., Wang, H., Chen, S., Luo, C., Xie, Q., et al. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115424 · Cited by 9
How myeloid cells shape experimental autoimmune encephalomyelitis: At the crossroads of outside‐in immunity
Diebold, M., Fehrenbacher, L., Frosch, M., & Prinz, M. (2023) · European Journal of Immunology · doi:10.1002/eji.202250234 · Cited by 10
“…for the receptor of granulocyte MU CSF) lack the ability to develop EAE [121], illustrating a central role of granulocyte MU CSF– dependent interactions between T cells and myeloid cells in disease initiation in the outside-in paradigm, reﬂected by observations in EAE [122–124] and MS [119, 125].”
Result
Investigation into Cardiac Myhc-α 334–352-Specific TCR Transgenic Mice Reveals a Role for Cytotoxic CD4 T Cells in the Development of Cardiac Autoimmunity
Sur, M., Rasquinha, M. T., Mone, K., Massilamany, C., Lasrado, N., Gurumurthy, C. B., Sobel, R. A., & Reddy, J. (2024) · Cells · doi:10.3390/cells13030234 · Cited by 10
“Similarly, Th cells producing GM-CSF (Th-GM cells) are reported to be proinflammatory in the induction of experimental autoimmune myocarditis [40] and other models [41–43].”
Background
Activation‐dependent cell death of human monocytes is a novel mechanism of fine‐tuning inflammation and autoimmunity
Däbritz, J., Weinhage, T., Varga, G., Wirth, T., Ehrchen, J., Barczyk-Kahlert, K., Roth, J., Schwarz, T., & Foell, D. (2016) · European Journal of Immunology · doi:10.1002/eji.201545802 · Cited by 10
Reduced TCR‐dependent activation through citrullination of a T‐cell epitope enhances Th17 development by disruption of the STAT3/5 balance
Tibbitt, C. A., Falconer, J., Stoop, J. N., van Eden, W., Robinson, J. H., & Hilkens, C. M. U. (2016) · European Journal of Immunology · doi:10.1002/eji.201546217 · Cited by 9
Studies of Mast Cells: Adventures in Serendipity
Brown, M. A. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00520 · Cited by 9
“Proc Natl Acad Sci U S A (2008) 105(46):18053–7.”
Targeting Nuclear Receptors for TH17-Mediated Inflammation: REV-ERBerations of Circadian Rhythm and Metabolism
Mosure, S., Wilson, A. N., & Solt, L. A. (2022) · Immunometabolism · doi:10.20900/immunometab20220006 · Cited by 10
Intrinsic STAT4 Expression Controls Effector CD4 T Cell Migration and Th17 Pathogenicity
Buzzelli, A. A., McWilliams, I. L., Shin, B., Bryars, M., & Harrington, L. E. (2023) · The Journal of Immunology · doi:10.4049/jimmunol.2200606 · Cited by 9
Exposure to inflammatory cytokines selectively limits GM ‐ CSF production by induced T regulatory cells
Reynolds, B. C., Turner, D. G., McPherson, R. C., Prendergast, C. T., Phelps, R. G., Turner, N. A., O’Connor, R. A., & Anderton, S. M. (2014) · European Journal of Immunology · doi:10.1002/eji.201444687 · Cited by 9
rs657075 (CSF2) Is Associated with the Disease Phenotype (BAS-G) of Ankylosing Spondylitis
Chen, W.-C., Wei, J. C., Lu, H.-F., Wong, H., Woon, P. Y., Hsu, Y.-W., Huang, J.-D., & Chang, W. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18010083 · Cited by 9
“On the other hand, the T helper Th17 cells require Csf2 to induce autoimmune encephalomyelitis or autoimmune neuroinflammation [38].”
Background
Granulocyte macrophage colony stimulating factor in virus-host interactions and its implication for immunotherapy
Bouzeineddine, N. Z., Philippi, A., Gee, K., & Basta, S. (2024) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2024.12.002 · Cited by 8
Interplay between fungal infections and autoimmunity: mechanisms and therapeutic perspectives
DiPalma, D. T., Lumbreras, M., & Shinohara, M. L. (2025) · EMBO Molecular Medicine · doi:10.1038/s44321-025-00262-y · Cited by 10
“…such as G-CSF, M-CSF, and GM-CSF, enhance myelopoiesis and fungal clearance (Bandera et al, 2008; Du et al, 2020; Nemunaitis et al, 1993), but GM-CSF is particularly linked to autoimmune diseases as a detrimental factor in MS (Codarri et al, 2011; El-Behi et al, 2011; McQualter et al, 2001).”
Chimeric HIV-1 Envelope Glycoproteins with Potent Intrinsic Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Activity*
Isik, G., van Montfort, T., Boot, M., Jiménez, V. C., Kootstra, N. A., & Sanders, R. W. (2013) · PLoS ONE · doi:10.1371/journal.pone.0060126 · Cited by 8
“In a first prototype chimeric molecule the V1V2 region of Env was replaced with the GM-CSF (EnvGM-CSF) [23], a pluripotent cytokine acting on different myeloid hematopoietic cells [45,46], dendritic cells [47], and Tcells [48], leading to enhanced T and B cell responses to Env.”
Background
Design principles of microparticle size and immunomodulatory factor formulation dictate antigen-specific amelioration of multiple sclerosis in a mouse model
Kwiatkowski, A. J., Helm, E. Y., Stewart, J. M., Leon, J., Drashansky, T. T., Avram, D., & Keselowsky, B. G. (2023) · Biomaterials · doi:10.1016/j.biomaterials.2023.122001 · Cited by 9
Insights into the advances in therapeutic drugs for neuroinflammation-related diseases
Luo, B. (2023) · International Journal of Neuroscience · doi:10.1080/00207454.2023.2260088 · Cited by 7
BHLHE40 Mediates Cross-Talk between Pathogenic TH17 Cells and Myeloid Cells during Experimental Autoimmune Encephalomyelitis
Cook, M. E., Shchukina, I., Lin, C., Bradstreet, T. R., Schwarzkopf, E. A., Jarjour, N. N., Webber, A. M., Zaitsev, K., Artyomov, M. N., & Edelson, B. T. (2023) · ImmunoHorizons · doi:10.4049/immunohorizons.2300042 · Cited by 7
Microbe driven T‐helper cell differentiation: lessons from Candida albicans and Staphylococcus aureus
Zielinski, C. E. (2014) · Experimental Dermatology · doi:10.1111/exd.12493 · Cited by 9
Cathepsin L regulates pathogenic CD4 T cells in experimental autoimmune encephalomyelitis
Shibamura‐Fujiogi, M., Yuki, K., & Hou, L. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.107425 · Cited by 8
Pertussis Toxin Inhibits Encephalitogenic T-Cell Infiltration and Promotes a B-Cell-Driven Disease during Th17-EAE
Maria, Z., Turner, E., Agasing, A. M., Kumar, G., & Axtell, R. C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22062924 · Cited by 9
“GM-CSF produced by the Th17 cells is essential for EAE induction [31,40] and IL17A contributes to the development of disease [41].”
Background
Sepsis and multiple sclerosis: Causative links and outcomes
Miljković, D. M., Stanisavljević, S., Jensen, I. J., Griffith, T. S., & Badovinac, V. P. (2021) · Immunology Letters · doi:10.1016/j.imlet.2021.07.008 · Cited by 8
Conformational Changes of RORγ During Response Element Recognition and Coregulator Engagement
Strutzenberg, T. S., Zhu, Y., Novick, S. J., Garcia-Ordoñez, R. D., Doebelin, C., He, Y., Chang, M. R., Kamenecka, T. M., Edwards, D. P., & Griffin, P. R. (2021) · Journal of Molecular Biology · doi:10.1016/j.jmb.2021.167258 · Cited by 9
Central Nervous System Resident Cells in Neuroinflammation: A Brave New World.
Peron, J. P. S., de Oliveira, D. H., N., W., Fickinger, A., de Oliveira, A. P. L., Lourenco Mychael, V., & Camar, N. O. S. (2012) · InTech eBooks · doi:10.5772/48161 · Cited by 8
T Cell-Derived GM-CSF, Regulation of Expression and Function
Sheng, W. (2015) · Immunome Research · doi:10.4172/1745-7580.1000098 · Cited by 8
“The important role of T cell-derived GM-CSF in EAE was further supported by studies from two groups that independently reported that GM-CSF secreted by IFN-γ-deficient or IL-17-deficient CD4+ T cells was sufficient for the induction of EAE [15,20].”
BackgroundResult
Novel therapeutic options in inflammatory cardiomyopathy
Kania, G., Błyszczuk, P., Müller‐Edenborn, B., & Eriksson, U. (2013) · Swiss Medical Weekly · doi:10.4414/smw.2013.13841 · Cited by 9
Strain specificities in cellular and molecular immunopathogenic mechanisms underlying development of experimental autoimmune encephalomyelitis in aged rats
Nacka-Aleksić, M., Stojić-Vukanić, Z., Pilipović, I., Vujnović, I., Bufan, B., Dimitrijević, M., & Leposavić, G. (2017) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2017.03.001 · Cited by 8
Deficiency of IL-1 receptor antagonist suppresses IL-10-producing B cells in autoimmune arthritis in an IL-17/Th17-dependent manner
Park, J., Kim, N., Lim, M., Kim, S., Hwang, S., Jung, K., Choi, J., Park, S., & Cho, M. (2018) · Immunology Letters · doi:10.1016/j.imlet.2018.05.003 · Cited by 8
IL-3 Is a Marker of Encephalitogenic T Cells, but Not Essential for CNS Autoimmunity
Lee, P. W., Xin, M., Pei, W., Yang, Y.-H., & Lovett-Racke, A. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01255 · Cited by 9
“Since the Il3 allele is located in the same gene cluster with Csf2 (encodes GMCSF) on chromosome 11 in mouse and chromosome 5 in human (Figure 1G) and GMCSF was found to be critical for encephalitogenic T cells (17, 21, 23, 24), we analyzed GMCSF+activated CD4 T cells via flow cytometry.”
Background
The Role of Th17 Cells in Immunopathogenesis of Neuroinflammatory Disorders
Pourgholaminejad, A., & Tahmasebinia, F. (2019) · Contemporary clinical neuroscience · doi:10.1007/978-3-030-19515-1_3 · Cited by 8
Signaling Pathways and Epigenetic Regulations in the Control ofRORγtExpression in T Helper 17 Cells
Tian, Y., Wu, Y., & Ni, B. (2014) · International Reviews of Immunology · doi:10.3109/08830185.2014.911858 · Cited by 7
Targeting Inflammatory T Helper Cells via Retinoic Acid-Related Orphan Receptor Gamma t Is Ineffective to Prevent Allo-Response-Driven Colitis
Buchele, V., Abendroth, B., Büttner-Herold, M., Vogler, T., Rothamer, J., Ghimire, S., Ullrich, E., Holler, E., Neurath, M., & Hildner, K. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01138 · Cited by 6
“In the light of the notion provided by recent studies showing in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis, that GM-CSF-expressing T cells are driven by IL-23, express the master regulator of Th17 development RORγt and hence putatively represent a Th17 cell subset (22, 23), our cu…”
Background
A Requirement of Protein Geranylgeranylation for Chemokine Receptor Signaling and Th17 Cell Function in an Animal Model of Multiple Sclerosis
Swan, G. A., Geng, J., Park, E., Ding, Q., Zhou, J., Walcott, C., Zhang, J. J., Huang, H.-I., Hammer, G. E., & Wang, D. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.641188 · Cited by 7

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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