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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Tbet or Continued RORγt Expression Is Not Required for Th17-Associated Immunopathology
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IκBNS Regulates Murine Th17 Differentiation during Gut Inflammation and Infection
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Background
REGγ controls Th17 cell differentiation and autoimmune inflammation by regulating dendritic cells
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Background
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BackgroundInfluential
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Background
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Background
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“[50-52] or Th17 cells alone [45-46, 49-51], could mediate EAE.”
Background
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“expression of this cytokine by CD4 T cells is essential for the development of EAE (18, 19).”
Background
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“This approach is currently investigated in phase II clinical trials in patients with rheumatoid arthritis in which two antibodies (MOR103 and KB003) designed to block GM-CSF signalling are being tested, after MOR103 demonstrated preliminary evidence of efficiency in this autoimmune disease [209].”
BackgroundInfluential
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“Some CD4+ T cells produce GM-CSF under inflammatory conditions (31,32).”
Background
IL-9 Controls Central Nervous System Autoimmunity by Suppressing GM-CSF Production
Yoshimura, S., Thomé, R., Konno, S., Mari, E. R., Rasouli, J., Hwang, D., Boehm, A., Lǐ, Y., Zhang, G., Ćirić, B., et al. (2019) · The Journal of Immunology · doi:10.4049/jimmunol.1801113 · Cited by 25
Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune encephalomyelitis
Luo, L., Hu, X., Dixon, M. L., Pope, B. J., Leavenworth, J. D., Raman, C., Meador, W. R., & Leavenworth, J. W. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02076-4 · Cited by 26
CD4 + T cells require Ikaros to inhibit their differentiation toward a pathogenic cell fate
Bernardi, C., Maurer, G., Ye, T., Marchal, P., Jost, B., Wissler, M., Maurer, U., Kastner, P., Chan, S. H., & Charvet, C. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2023172118 · Cited by 25
T helper cell populations: As flexible as the skin?
Waisman, A. (2011) · European Journal of Immunology · doi:10.1002/eji.201141938 · Cited by 25
Stability of T-cell lineages in autoimmune diseases
Raphael, I., & Forsthuber, T. (2012) · Expert Review of Clinical Immunology · doi:10.1586/eci.12.22 · Cited by 22
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Cytokine-Neuroantigen Fusion Proteins as a New Class of Tolerogenic, Therapeutic Vaccines for Treatment of Inflammatory Demyelinating Disease in Rodent Models of Multiple Sclerosis
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“These findings indicate that the high affinity docking of the cytokine domain to cytokine receptors on APC was the key event for potentiated antigen recognition.”
Background
Recent Advances in Monoclonal Antibody Therapies for Multiple Sclerosis
Wootla, B., Watzlawik, J. O., Stavropoulos, N., Wittenberg, N. J., Dasari, H., Abdelrahim, M. A., Henley, J. R., Oh, S., Warrington, A. E., & Rodriguez, M. (2016) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2016.1158809 · Cited by 25
“Under these conditions, breakdown of BBB may in fact be beneficial, as this will result in an increased influx of NAbs or drugs with reparative properties to target and protect intrinsic cells of the CNS.[125] Nonetheless, the emergence of new molecules or techniques that would promote easier and safer crossing of the…”
BackgroundInfluential
Increased interleukin‐23 receptor ( IL ‐23R) expression is associated with disease severity in acute‐on‐chronic liver failure
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“GM-CSF has also been identified as an important cytokine that contributes to the pathogenicity of inflammatory T cells in EAE by inducing activation and recruitment of innate immune cells (25, 26).”
Background
Higher Serum CCN3 Is Associated with Disease Activity and Inflammatory Markers in Rheumatoid Arthritis
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“TNF-α and IFN-γ , which are Th1-related cytokines, are considered as the key proin ﬂ ammatory cytokines in the progression of human RA [4, 5].”
Adult Onset Still's Disease and Autoinflammation
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Subclinical CNS Inflammation as Response to a Myelin Antigen in Humanized Mice
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“The increased levels for human GM-CSF and IFN-γ mRNA were CNS-specific as mRNA levels of total splenocytes showed only low levels of cytokine expression in both groups.”
BackgroundInfluential
The role of chemokines in adjusting the balance between CD4+ effector T cell subsets and FOXp3-negative regulatory T cells
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Induction of Peripheral Tolerance in Ongoing Autoimmune Inflammation Requires Interleukin 27 Signaling in Dendritic Cells
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G-CSF and Neutrophils Are Nonredundant Mediators of Murine Experimental Autoimmune Uveoretinitis
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“As seen in the previous experiments, TNF was also significantly reduced, whereas GM-CSF was not.”
BackgroundInfluential
Mast cells and angiogenesis in multiple sclerosis
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Brain-homing CD4 + T cells display glucocorticoid-resistant features in MS
Koetzier, S. C., van Langelaar, J., Blok, K. M., van den Bosch, T. P. P., Wierenga‐Wolf, A. F., Melief, M., Pol, K., Siepman, T. A. M., Verjans, G. M. G. M., Smolders, J., et al. (2020) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000000894 · Cited by 22
Deficiency of IL-27 Signaling Exacerbates Experimental Autoimmune Uveitis with Elevated Uveitogenic Th1 and Th17 Responses
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“GM-CSF has been shown to be an important pathogenic cytokine from Th17 cells in neuroinflammation [27].”
Background
Contact-Dependent Granzyme B-Mediated Cytotoxicity of Th17-Polarized Cells Toward Human Oligodendrocytes
Jamann, H., Cui, Q., Desu, H. L., Pernin, F., Tastet, O., Halaweh, A., Farzam‐kia, N., Mamane, V. H., Ouédraogo, O., Cleret‐Buhot, A., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.850616 · Cited by 24
Neuroinflammation: Extinguishing a blaze of T cells
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Th17 Cells Induce a Distinct Graft Rejection Response That Does Not Require IL-17A
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“It is also possible that neither IL-17A nor IL-17F are essential to the rejection process mediated by Th17 cells (59), with granulocytemacrophage colony stimulating factor (CSF2) (60,61) and IL-22 (62) as other candidates to be excluded.”
Background
Granulocyte-Macrophage Colony Stimulatory Factor Enhances the Pro-Inflammatory Response of Interferon-γ-Treated Macrophages to Pseudomonas aeruginosa Infection
Singh, S., Barr, H. L., Liu, Y., Robins, A., Heeb, S., Williams, P. M., Fogarty, A., Cámara, M., & Martínez‐Pomares, L. (2015) · PLoS ONE · doi:10.1371/journal.pone.0117447 · Cited by 23
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Estrogen Signaling in Bystander Foxp3neg CD4+ T Cells Suppresses Cognate Th17 Differentiation in Trans and Protects from Central Nervous System Autoimmunity
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“genic Th17 cells is essential for the induction of neuroinflammation in EAE (34, 35).”
Background
Mechanisms and functions of IL-17 signaling in renal autoimmune diseases
Schmidt, T., Luebbe, J., Paust, H., & Panzer, U. (2018) · Molecular Immunology · doi:10.1016/j.molimm.2018.09.005 · Cited by 23
“TH17 cells are characterized by the transcription factors RORγt and STAT3 (Ivanov et al., 2006; Nurieva et al., 2007), which orchestrate the production of the proinflammatory cytokines IL-17 A (referred to as IL-17), IL-17 F, IL-22, and GM-CSF (Codarri et al., 2011; Zenewicz et al., 2007), as well as the expression of…”
Background
Signature cytokine-associated transcriptome analysis of effector γδ T cells identifies subset-specific regulators of peripheral activation
Inácio, D., Amado, T., Pamplona, A., Sobral, D., Cunha, C., Santos, R. F., Oliveira, L., Rouquié, N., Carmo, A. M., Lesourne, R., et al. (2025) · Nature Immunology · doi:10.1038/s41590-024-02073-8 · Cited by 24
“…mice at the peak of experimental autoimmune encephalomyelitis (EAE; SRA-SUB14032445), given that type 1 helper T (T H 1) cells and IL-17-producing helper T (T H 17) cells are not readily found at steady state but require an inflammatory challenge for their differentiation and expansion 11 .”
Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Insights into pathogenesis and biomarkers of prognosis
Andersen, J., & Brilot, F. (2025) · Seminars in Immunology · doi:10.1016/j.smim.2025.101944 · Cited by 22
Progress and Prospects of Regulatory Functions Mediated by Nitric Oxide on Immunity and Immunotherapy
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Immune response during interferon beta-1b treatment in patients with multiple sclerosis who experienced relapses and those who were relapse-free in the START study
Dhib-Jalbut, S. S., Sumandeep, S., Valenzuela, R. M., Ito, K., Patel, P., & Rametta, M. (2012) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2012.08.012 · Cited by 22
“Nevertheless, Th17 cells are pro-inflammatory as they have been shown to damage the BBB (Kebir et al., 2007) and also stimulate GM-CSF producing cells (Codarri et al., 2011).”
Depletion of CD4+ CD25+ regulatory T cells confers susceptibility to experimental autoimmune encephalomyelitis (EAE) in GM‐CSF‐deficient Csf2−/− mice
Ghosh, D., Curtis, A. D., Wilkinson, D., & Mannie, M. (2016) · Journal of Leukocyte Biology · doi:10.1189/jlb.3a0815-359r · Cited by 20
“not mediate the adoptive transfer of EAE [14, 16].”
Role of the epigenetic factor Sirt7 in neuroinflammation and neurogenesis
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Interleukin-27 Gene Therapy Prevents the Development of Autoimmune Encephalomyelitis but Fails to Attenuate Established Inflammation due to the Expansion of CD11b+Gr-1+ Myeloid Cells
Zhu, J., Liu, J.-Q., Liu, Z., Wu, L., Shi, M., Zhang, J., Davis, J. P., & Bai, X. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00873 · Cited by 22
“We also observed that AAV-IL27 treatment inhibited the frequencies of GM-CSF-producing T cells in peripheral lymphoid organs in EAE protected mice, which is consistent with the known function of IL-27 in inhibiting GM-CSF production by T cells (17, 24).”
MethodResultInfluential
CNS-Specific Synthesis of Interleukin 23 Induces a Progressive Cerebellar Ataxia and the Accumulation of Both T and B Cells in the Brain: Characterization of a Novel Transgenic Mouse Model
Nitsch, L., Zimmermann, J., Krauthausen, M., Hofer, M. J., Saggu, R., Petzold, G. C., Heneka, M. T., Getts, D. R., Becker, A. J., Campbell, I. L., et al. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-1640-0 · Cited by 21
RORγ Agonists Enhance the Sustained Antitumor Activity through Intrinsic Tc17 Cytotoxicity and Tc1 Recruitment
Liu, X., Zawidzka, E. M., Li, H., Lesch, C. A., Dunbar, J. E., Bousley, D., Zou, W., Hu, X., & Carter, L. (2019) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0714 · Cited by 22
“IL17A and IL17F bind to IL17 receptors on endothelial cells, stromal cells, and tumor cells (23) and induce the production of various chemokines such as CCL20, CXCL9, and CXCL10, which recruit monocytes, neutrophils, natural killer (NK) cells, and CD8þ T cells into the tumor microenvironment (24, 25).”
Background

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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