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

doi:10.1038/ni.2027

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

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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GM-CSF is essential for the development and progression of EAE; mice deficient in GM-CSF are resistant to EAE induction, and blockade of GM-CSF in wild-type mice suppresses ongoing disease.
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The Immunobiology of the Interleukin-12 Family: Room for Discovery
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“Th17 cells that produce GM-CSF are present in the blood of healthy humans and MS patients (Kara et al., 2015), but in humans, IL-23 appears to limit GM-CSF production (Noster et al., 2014).”
Influential
CNS inflammation and neurodegeneration
Chitnis, T., & Weiner, H. L. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90609 · Cited by 484 · see citing works
“In EAE, GM-CSF production by Th17 cells activates effector mononuclear phagocytes (89).”
Background
MAFG-driven astrocytes promote CNS inflammation
Wheeler, M. A., Clark, I. C., Tjon, E. C., Li, Z., Zandee, S. E. J., Couturier, C. P., Watson, B. R., Scalisi, G., Alkwai, S., Rothhammer, V., et al. (2020) · Nature · doi:10.1038/s41586-020-1999-0 · Cited by 501 · see citing works
GM-CSF, IL-3, and IL-5 Family of Cytokines: Regulators of Inflammation
Dougan, M. L., Dranoff, G., & Dougan, S. K. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.022 · Cited by 463 · see citing works
The IL-23-IL-17 axis in inflammatory arthritis
Lubberts, E. (2015) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2015.53 · Cited by 442 · see citing works
Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids
Ramesh, R., Kozhaya, L., McKevitt, K., Djuretic, I. M., Carlson, T. J., Quintero, M. A., McCauley, J. L., Abreu, M. T., Unutmaz, D., & Sundrud, M. S. (2014) · The Journal of Experimental Medicine · doi:10.1084/jem.20130301 · Cited by 434 · see citing works
“Furthermore, IL-23 has been reported to induce GM-CSF expression in Th17 cells, and GM-CSF–deficient Th17 cells fail to induce adoptively transferred EAE (Codarri et al., 2011).”
BackgroundInfluential
Oligodendrocyte precursor cells present antigen and are cytotoxic targets in inflammatory demyelination
Kirby, L., Jin, J., Cardona, J. G., Smith, M. D., Martin, K. A., Wang, J., Strasburger, H., Herbst, L., Alexis, M., Karnell, J., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11638-3 · Cited by 436 · see citing works
GM-CSF Controls Nonlymphoid Tissue Dendritic Cell Homeostasis but Is Dispensable for the Differentiation of Inflammatory Dendritic Cells
Greter, M., Helft, J., Chow, A., Hashimoto, D., Mortha, A., Agudo-Cantero, J., Bogunovic, M., Gautier, E. L., Miller, J., Leboeuf, M., et al. (2012) · Immunity · doi:10.1016/j.immuni.2012.03.027 · Cited by 433 · see citing works
“Csf-2 also plays a pivotal role for the development of experimental autoimmune encephalomyelitis (EAE) (Codarri et al., 2011).”
Background
The plasticity of human Treg and Th17 cells and its role in autoimmunity
Kleinewietfeld, M., & Hafler, D. A. (2013) · Seminars in Immunology · doi:10.1016/j.smim.2013.10.009 · Cited by 389 · see citing works
“Of note, recent studies suggested that the cytokine GMCSF plays a fundamental role in the pathogenicity of Th17 cells in EAE [38, 39].”
BackgroundInfluential
Essentials of Th17 cell commitment and plasticity
Muranski, P. J., & Restifo, N. P. (2013) · Blood · doi:10.1182/blood-2012-09-378653 · Cited by 386 · see citing works
“Blockade of GM-CSF signaling effectively protected mice from autoimmunity.(104) Nevertheless, despite the latest emphasis on Th17 cells, both Th1 and Th17 cells can cause EAE and murine uveitis manifestations, albeit with distinct histopathological features.”
Background
NF-κB in inflammation and renal diseases
Zhang, H., & Sun, S.-C. (2015) · Cell & Bioscience · doi:10.1186/s13578-015-0056-4 · Cited by 383 · see citing works
Microglia Require CD4 T Cells to Complete the Fetal-to-Adult Transition
Pasciuto, E., Burton, O. T., Roca, C. P., Lagou, V., Rajan, W. D., Theys, T., Mancuso, R., Tito, R. Y., Kouser, L., Callaerts-Vegh, Z., et al. (2020) · Cell · doi:10.1016/j.cell.2020.06.026 · Cited by 368 · see citing works
“CD4 T cells are best known in the neurological context as potent mediators of autoimmune diseases, such as multiple sclerosis, where oligodendrocytes are the target (Codarri et al., 2011; Komuczki et al., 2019), and narcolepsy, where hypocretin neurons are killed (Hartmann et al.”
Background
Innate Lymphoid Cells in Inflammation and Immunity
McKenzie, A. N. J., Spits, H., & Eberl, G. (2014) · Immunity · doi:10.1016/j.immuni.2014.09.006 · Cited by 366 · see citing works
High-dimensional analysis of the murine myeloid cell system
Becher, B., Schlitzer, A., Chen, J.-M., Mair, F., Sumatoh, H., Teng, K., Low, D., Ruedl, C., Riccardi-Castagnoli, P., Poidinger, M., et al. (2014) · Nature Immunology · doi:10.1038/ni.3006 · Cited by 357 · see citing works
Guselkumab in biologic-naive patients with active psoriatic arthritis (DISCOVER-2): a double-blind, randomised, placebo-controlled phase 3 trial
Mease, P. J., Rahman, P., Gottlieb, A. B., Kollmeier, A. P., Hsia, E. C., Xu, X. L., Sheng, S., Agarwal, P., Zhou, B., Zhuang, Y., et al. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30263-4 · Cited by 358 · see citing works
Neuroinflammatory TNFα Impairs Memory via Astrocyte Signaling
Habbas, S., Santello, M., Becker, D., Stubbe, H., Zappia, G., Liaudet, N., Klaus, F. R., Kollias, G., Fontana, A., Pryce, C. R., et al. (2015) · Cell · doi:10.1016/j.cell.2015.11.023 · Cited by 347 · see citing works
“Our studies were performed in the EAE mouse model, using an adoptive transfer induction protocol (AT-EAE, Codarri et al. (2011); see Experimental Procedures), which allows the EAE CNS pathology to develop effectively also in TNFR1-deficient mice.”
InfluentialSelf-citation
Neuroimmune regulation of microglial activity involved in neuroinflammation and neurodegenerative diseases
González, H., Elgueta, D., Montoya, A., & Pacheco, R. (2014) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2014.07.012 · Cited by 352 · see citing works
Methionine Metabolism Shapes T Helper Cell Responses through Regulation of Epigenetic Reprogramming
Roy, D. G., Chen, J., Mamane, V. H., Ma, E. H., Muhire, B. M., Sheldon, R. D., Shorstova, T., Koning, R., Johnson, R. M., Esaulova, E., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.01.006 · Cited by 347 · see citing works
Targeting Th17 cells in autoimmune diseases
Yang, J., Sundrud, M. S., Skepner, J. E., & Yamagata, T. (2014) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2014.07.006 · Cited by 348 · see citing works
Gut-licensed IFNγ+ NK cells drive LAMP1+TRAIL+ anti-inflammatory astrocytes
Sanmarco, L. M., Wheeler, M. A., Gutiérrez-Vázquez, C., Polonio, C. M., Linnerbauer, M., Pinho-Ribeiro, F. A., Li, Z., Giovannoni, F., Batterman, K. V., Scalisi, G., et al. (2021) · Nature · doi:10.1038/s41586-020-03116-4 · Cited by 331 · see citing works
Th1 and Th17 Cells in Tuberculosis: Protection, Pathology, and Biomarkers
Lyadova, I. V., & Panteleev, A. V. (2015) · Mediators of Inflammation · doi:10.1155/2015/854507 · Cited by 330 · see citing works
“IL-23, IL1𝛽, and TNF-𝛼 maintain and amplify Th17 cells.”
Background
Intestinal Interleukin-17 Receptor Signaling Mediates Reciprocal Control of the Gut Microbiota and Autoimmune Inflammation
Kumar, P., Monin, L., Castillo, P., Elsegeiny, W., Horne, W., Eddens, T., Vikram, A., Good, M., Schoenborn, A. A., Bibby, K., et al. (2016) · Immunity · doi:10.1016/j.immuni.2016.02.007 · Cited by 326 · see citing works
“Next, we examined IL-17 and other encephalitogenic factors such as the cytokines GM-CSF and G-CSF, which have been implicated in EAE severity (Codarri et al., 2011; Rumble et al., 2015).”
Influential
Melatonin Contributes to the Seasonality of Multiple Sclerosis Relapses
Farez, M. F., Mascanfroni, I. D., Méndez-Huergo, S. P., Yeste, A., Murugaiyan, G., Garo, L. P., Balbuena Aguirre, M. E., Patel, B., Ysrraelit, M. C., Zhu, C., et al. (2015) · Cell · doi:10.1016/j.cell.2015.08.025 · Cited by 318 · see citing works
Advances in Meningeal Immunity
Rua, R., & McGavern, D. B. (2018) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2018.04.003 · Cited by 326 · see citing works
IFN-γ-dependent activation of the brain’s choroid plexus for CNS immune surveillance and repair
Kunis, G., Baruch, K., Rosenzweig, N., Kertser, A., Miller, O., Berkutzki, T., & Schwartz, M. (2013) · Brain · doi:10.1093/brain/awt259 · Cited by 321 · see citing works
“Granulocyte-macrophage colony-stimulating factor (GM-CSF) secreting helper T cells were shown to be highly ence- phalitogenic (Codarri et al., 2011), we therefore also examined whether this cell population is present in the choroid plexus, and found it to be absent in the naı̈ve choroid plexus…”
Background
GM-CSF in inflammation
Hamilton, J. A. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20190945 · Cited by 310 · see citing works
The IL-1β phenomena in neuroinflammatory diseases
Mendiola, A. S., & Cardona, A. E. (2017) · Journal of Neural Transmission · doi:10.1007/s00702-017-1732-9 · Cited by 311 · see citing works
“Further EAE studies identified a critical role of IL1b and IL-23 in regulating the production of Th17-derived GM-CSF (transcribed from Csf2), a non-redundant cyto- kine required for T cells to become encephalitogenic (Codarri et al. 2011; El-Behi et al. 2011; Mufazalov et al. 2016).”
Background
The Role of Iron Regulation in Immunometabolism and Immune-Related Disease
Cronin, S. J. F., Woolf, C. J., Weiss, G., & Penninger, J. M. (2019) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2019.00116 · Cited by 299 · see citing works
“Mice deficient in GM-CSF are resistant to EAE induction, and blockade of GM-CSF in wild-type mice suppresses ongoing disease (McQualter et al., 2001; Codarri et al., 2011).”
Background
Cross-Talk Between Antigen Presenting Cells and T Cells Impacts Intestinal Homeostasis, Bacterial Infections, and Tumorigenesis
Gaudino, S. J., & Kumar, P. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00360 · Cited by 304 · see citing works
“Likewise, IL-23 signaling has been associated with increased expression of RORγt and production of GM-CSF, an essential cytokine for the progression of autoimmunity, by Th17 cells (63).”
Background
Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis
Cao, Y., Goods, B. A., Raddassi, K., Nepom, G. T., Kwok, W. W., Love, J. C., & Hafler, D. A. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aaa8038 · Cited by 290 · see citing works
“Recently, it was shown that GM-CSF plays a pathogenic role in EAE pathology (14, 15).”
Plasticity of Human CD4 T Cell Subsets
Geginat, J., Paroni, M., Maglie, S., Alfen, J. S., Kastirr, I., Gruarin, P., Simone, M. C. D., Pagani, M., & Abrignani, S. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00630 · Cited by 289 · see citing works
“A particular relevant cytokine in the pathogenesis of experimental autoimmunity is GM-CSF, which is induced by IL-1β, IL-23, and ROR-γt in mice (102, 129).”
Background
TH17 cell heterogeneity and its role in tissue inflammation
Schnell, A., Littman, D. R., & Kuchroo, V. K. (2023) · Nature Immunology · doi:10.1038/s41590-022-01387-9 · Cited by 286 · see citing works
PKM2 promotes Th17 cell differentiation and autoimmune inflammation by fine-tuning STAT3 activation
Damasceno, L. E. A., Prado, D. D. S., Veras, F. P., Fonseca, M. M., Toller-Kawahisa, J. E., Rosa, M. H., Públio, G. A., Martins, T. V., Ramalho, F. S., Waisman, A., et al. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20190613 · Cited by 289 · see citing works
“In support of this, we also demonstrated that GM-CSF, another pathogenic Th17 cell signature cytokine (Codarri et al., 2011; El-Behi et al., 2011), was similarly reduced in mice lacking PKM2 in T cells during EAE.”
Background
Colony stimulating factors and myeloid cell biology in health and disease
Hamilton, J. A., & Achuthan, A. (2013) · Trends in Immunology · doi:10.1016/j.it.2012.08.006 · Cited by 285 · see citing works
Recent advances in the IL-17 cytokine family
Gaffen, S. L. (2011) · Current Opinion in Immunology · doi:10.1016/j.coi.2011.07.006 · Cited by 283 · see citing works
“Recent findings indicate that GM-CSF is another Th17-derived cytokine that contributes to the inflammatory pathology of Th17 cells, based on data from EAE models [2,3].”
Macrophage subsets and microglia in multiple sclerosis
Bogie, J. F. J., Stinissen, P., & Hendriks, J. J. A. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1310-2 · Cited by 279 · see citing works
Innate lymphoid cells integrate stromal and immunological signals to enhance antibody production by splenic marginal zone B cells
Magri, G., Miyajima, M., Bascones, S., Mortha, A., Puga, I., Cassis, L., Barra, C., Comerma, L., Chudnovskiy, A., Gentile, M., et al. (2014) · Nature Immunology · doi:10.1038/ni.2830 · Cited by 280 · see citing works
The tumour microenvironment harbours ontogenically distinct dendritic cell populations with opposing effects on tumour immunity
Laoui, D., Keirsse, J., Morias, Y., van Overmeire, E., Geeraerts, X., Elkrim, Y., Kiss, M., Bolli, E., Lahmar, Q., Sichien, D., et al. (2016) · Nature Communications · doi:10.1038/ncomms13720 · Cited by 255 · see citing works
Role of Th17 cells in the pathogenesis of CNS inflammatory demyelination
Rostami, A. M., & Ćirić, B. (2013) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2013.03.002 · Cited by 275 · see citing works
“made a similar observation, and in addition found that RORγt is required for production of GM-CSF by Th cells (74).”
Background
T cell responses in the central nervous system
Korn, T., & Kallies, A. (2017) · Nature Reviews Immunology · doi:10.1038/nri.2016.144 · Cited by 268 · see citing works
Stem-like intestinal Th17 cells give rise to pathogenic effector T cells during autoimmunity
Schnell, A., Huang, L., Singer, M., Singaraju, A., Barilla, R. M., Regan, B. M. L., Bollhagen, A., Thakore, P. I., Dionne, D., Delorey, T. M., et al. (2021) · Cell · doi:10.1016/j.cell.2021.11.018 · Cited by 268 · see citing works
T-cell-mediated regulation of neuroinflammation involved in neurodegenerative diseases
González, H., & Pacheco, R. (2014) · Journal of Neuroinflammation · doi:10.1186/s12974-014-0201-8 · Cited by 270 · see citing works
Signal transducer and activator of transcription-3/suppressor of cytokine signaling-3 (STAT3/SOCS3) axis in myeloid cells regulates neuroinflammation
Qin, H., Yeh, W.-I., Sarno, P. D., Holdbrooks, A. T., Liu, Y., Muldowney, M., Reynolds, S. L., Yanagisawa, L. L., Fox, T. H., Park, K., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1117218109 · Cited by 266 · see citing works
“Th1 cells in turn produce IFN-γ and GM-CSF, whereas Th17 cells produce GMCSF (32, 33), which will sustain the M1 phenotype, establishing a feed-forward regulatory loop for M1, Th1, and Th17 cells.”
Background
Dual Role of GM-CSF as a Pro-Inflammatory and a Regulatory Cytokine: Implications for Immune Therapy
Bhattacharya, P., Budnick, I., Singh, M., Thiruppathi, M., Alharshawi, K., Elshabrawy, H. A., Holterman, M., & Prabhakar, B. S. (2015) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2014.0149 · Cited by 264 · see citing works
Targeting GM-CSF in inflammatory diseases
Wicks, I. P., & Roberts, A. W. (2015) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2015.161 · Cited by 261 · see citing works
Interleukin-17 in chronic inflammatory neurological diseases
Milovanovic, J., Arsenijevic, A., Stojanovic, B., Kanjevac, T., Arsenijevic, D., Radosavljevic, G., Milovanovic, M., & Arsenijevic, N. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00947 · Cited by 250 · see citing works
“Findings indicating that GM-CSF has the key role in the encephalitogenic potential of Th17 cells in mice (74, 170, 171), specifically, increased levels of GM-CSF in the cerebrospinal fluid and serum of active MS patients with the relapsing-remitting type of the disease and increased secretion of GM-CSF from T cells is…”
Background
Interleukin-17A Serves a Priming Role in Autoimmunity by Recruiting IL-1β-Producing Myeloid Cells that Promote Pathogenic T Cells
McGinley, A. M., Sutton, C. E., Edwards, S. C., Leane, C. M., DeCourcey, J., Teijeiro, A., Hamilton, J. A., Boon, L., Djouder, N., & Mills, K. H. G. (2020) · Immunity · doi:10.1016/j.immuni.2020.01.002 · Cited by 248 · see citing works
“GM-CSF, produced by Th1 and Th17 cells, was also shown to be a key pathogenic cytokine in EAE (Codarri et al., 2011; El-Behi et al., 2011).”
BackgroundMethod
MicroRNA-21 promotes Th17 differentiation and mediates experimental autoimmune encephalomyelitis
Murugaiyan, G., da Cunha, A. P., Ajay, A. K., Joller, N., Garo, L. P., Kumaradevan, S., Yosef, N., Vaidya, V. S., & Weiner, H. L. (2015) · Journal of Clinical Investigation · doi:10.1172/jci74347 · Cited by 239 · see citing works
Th17 Response and Inflammatory Autoimmune Diseases
Waite, J. C., & Skokos, D. (2011) · International Journal of Inflammation · doi:10.1155/2012/819467 · Cited by 239 · see citing works
Effector Functions of CD4+ T Cells at the Site of Local Autoimmune Inflammation—Lessons From Rheumatoid Arthritis
Chemin, K., Gerstner, C., & Malmström, V. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00353 · Cited by 235 · see citing works
“While GM-CSF appears to be a critical component of Th17 pathogenicity in the experimental autoimmune encephalomyelitis (EAE) mouse model (78), it is associated with the Th1 axis in multiple sclerosis (79).”
Background
ILC3 GM-CSF production and mobilisation orchestrate acute intestinal inflammation
Pearson, C., Thornton, E., McKenzie, B., Schaupp, A., Huskens, N., Griseri, T., West, N., Tung, S., Seddon, B., Uhlig, H., et al. (2016) · eLife · doi:10.7554/elife.10066 · Cited by 218 · see citing works
“Recent studies have focussed on the role of GM-CSF as an important mediator of IL-23 driven tissue inflammation (Codarri et al., 2011; El-Behi et al., 2011; Griseri et al., 2012).”
Background
GM-CSF-based treatments in COVID-19: reconciling opposing therapeutic approaches
Lang, F. M., Lee, M.-C., Teijaro, J. R., Becher, B., & Hamilton, J. A. (2020) · Nature reviews. Immunology · doi:10.1038/s41577-020-0357-7 · Cited by 232 · see citing works
IL-17 and GM-CSF Expression Are Antagonistically Regulated by Human T Helper Cells
Noster, R., Riedel, R., Mashreghi, M., Radbruch, H., Harms, L., Haftmann, C., Chang, H., Radbruch, A., & Zielinski, C. E. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3008706 · Cited by 231 · see citing works
“cytokines inhibit the polarization of GM-CSF–producing cells (9, 10).”
BackgroundResultInfluential
Toll-like receptor 4 signaling in T cells promotes autoimmune inflammation
Reynolds, J., Martinez, G., Chung, Y., & Dong, C. (2012) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1120585109 · Cited by 237 · see citing works
“Recent work has shown that IL-23-driven production of GMCSF by Th17 cells is critical for the development of EAE (23, 24).”
Background
Neutrophils Mediate Blood–Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases
Aubé, B., Lévesque, S. A., Paré, A., Chamma, É., Kébir, H., Gorina, R., Lécuyer, M., Alvarez, J. I., Koninck, Y. D., Engelhardt, B., et al. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1400401 · Cited by 229 · see citing works
The many faces of Th17 cells
Peters, A., Lee, Y., & Kuchroo, V. K. (2011) · Current Opinion in Immunology · doi:10.1016/j.coi.2011.08.007 · Cited by 232 · see citing works
Induction of autoimmune disease by deletion of CTLA-4 in mice in adulthood
Klocke, K., Sakaguchi, S., Holmdahl, R., & Wing, K. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1603892113 · Cited by 232 · see citing works
“Proinflammatory cytokines in general and GMCSF in particular are crucial for development of EAE (42).”
Background
Cardiac myosin-Th17 responses promote heart failure in human myocarditis
Myers, J. M., Cooper, L. T., Kem, D. C., Stavrakis, S., Kosanke, S. D., Shevach, E. M., Fairweather, D., Stoner, J. A., Cox, C. J., & Cunningham, M. W. (2016) · JCI Insight · doi:10.1172/jci.insight.85851 · Cited by 230 · see citing works
“Given that IL-23 promotes inflammation through GM-CSF secretion from Th17 cells (52, 53), we determined if IL-23, GM-CSF, and GM-CSF lymphocytes were elevated in myocarditis/DCM.”
The GM – CSF / IL‐3 / IL‐5 cytokine receptor family: from ligand recognition to initiation of signaling
Broughton, S. E., Dhagat, U., Hercus, T. R., Nero, T. L., Grimbaldeston, M. A., Bonder, C. S., Lopez, A. F., & Parker, M. W. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01164.x · Cited by 230 · see citing works
“and adaptive immune responses to infection (6, 29, 30) and inflammatory diseases (9, 31), such as asthma (32–34), rheumatoid arthritis (35–37), multiple sclerosis (38, 39), and autoimmune glomerulonephritis (40, 41).”
Background
Roles of GM-CSF in the Pathogenesis of Autoimmune Diseases: An Update
Lotfi, N., Thomé, R., Rezaei, N., Zhang, G., Rezaei, A., Rostami, A. M., & Esmaeil, N. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01265 · Cited by 229 · see citing works
The Th17 family: flexibility follows function
Basu, R., Hatton, R. D., & Weaver, C. T. (2013) · Immunological Reviews · doi:10.1111/imr.12035 · Cited by 229 · see citing works
“Importantly, although T-bet is essential for pathogenicity of Th17-derived effectors, its absence did not impair GM-CSF expression (87), which was shown to be RORct dependent in one of the studies (87) but not the other (88).”
BackgroundInfluential
Multiple sclerosis: Neuroimmune crosstalk and therapeutic targeting
Charabati, M., Wheeler, M. A., Weiner, H. L., & Quintana, F. J. (2023) · Cell · doi:10.1016/j.cell.2023.03.008 · Cited by 229 · see citing works
Pouring fuel on the fire: Th17 cells, the environment, and autoimmunity
Burkett, P. R., zu Hörste, G. M., & Kuchroo, V. K. (2015) · Journal of Clinical Investigation · doi:10.1172/jci78085 · Cited by 221 · see citing works
Adaptive Immunity to Fungi
Wüthrich, M., Deepe, G. S., & Klein, B. S. (2012) · Annual Review of Immunology · doi:10.1146/annurev-immunol-020711-074958 · Cited by 225 · see citing works
CD 4+ T‐cell subsets in intestinal inflammation
Shale, M., Schiering, C., & Powrie, F. M. (2013) · Immunological Reviews · doi:10.1111/imr.12039 · Cited by 222 · see citing works
T helper 17.1 cells associate with multiple sclerosis disease activity: perspectives for early intervention
van Langelaar, J., de Vries, R. M. V. D. V., Janssen, M., Wierenga‐Wolf, A. F., Spilt, I. M., Siepman, T. A. M., Dankers, W., Verjans, G. M. G. M., de Vries, H. E., Lubberts, E., et al. (2018) · Brain · doi:10.1093/brain/awy069 · Cited by 224 · see citing works
“…not IL-17-producing Th17 cells as the most pro-inflammatory subset in early multiple sclerosis, and also agrees with the minimal influence of IL-17 and strong impact of GM-CSF on experimental autoimmune encephalomyelitis induction (Ponomarev et al., 2007; Haak et al., 2009; Codarri et al., 2011).”
Background
Experimental Autoimmune Encephalomyelitis (EAE) as Animal Models of Multiple Sclerosis (MS)
Glatigny, S., & Bettelli, E. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a028977 · Cited by 247 · see citing works
“Interestingly, IL-23 was also shown to induce the expression of GM-CSF in CD4 T cells (Codarri et al. 2011; El-Behi et al. 2011).”
BackgroundInfluential
Th17 cell development: from the cradle to the grave
Zuniga, L. A., JAIN, R. K., Haines, C., & Cua, D. J. (2013) · Immunological Reviews · doi:10.1111/imr.12036 · Cited by 218 · see citing works
“In addition, IL27 also inhibits GM-CSF expression by Th17 cells (46), the mechanism of which is not clearly understood, but may be due to suppression of RORct or ablation of IL-23 signaling.”
Background
Cholesterol Accumulation in Dendritic Cells Links the Inflammasome to Acquired Immunity
Westerterp, M., Gautier, E. L., Ganda, A., Molusky, M. M., Wang, W., Fotakis, P., Wang, N., Randolph, G. J., D'Agati, V. D., Yvan-Charvet, L., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.04.005 · Cited by 218 · see citing works
“Previous studies have suggested that GMCSF induces the secretion of these cytokines by DCs (Codarri et al., 2011; El-Behi et al., 2011; Sonderegger et al., 2008), linking GM-CSF signaling with autoimmunity.”
Background
GM-CSF: An immune modulatory cytokine that can suppress autoimmunity
Bhattacharya, P., Thiruppathi, M., Elshabrawy, H. A., Alharshawi, K., Kumar, P., & Prabhakar, B. S. (2015) · Cytokine · doi:10.1016/j.cyto.2015.05.030 · Cited by 208 · see citing works
“These data suggested that EAE reactive T cells activate the microglial cells through the secretion of GM-CSF (132-134).”
Background

The encephalitogenicity of TH17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF
El-Behi, M., Ciric, B., Dai, H., Yan, Y., Cullimore, M., Safavi, F., Zhang, G.-X., Dittel, B. N., & Rostami, A. (2011) · Nature Immunology · doi:10.1038/ni.2031 · Cited by 1,071 · see citing works
STAT5 programs a distinct subset of GM-CSF-producing T helper cells that is essential for autoimmune neuroinflammation
Sheng, W., Yang, F., Zhou, Y., Yang, H., Low, P. Y., Kemeny, D. M., Tan, P., Moh, A., Kaplan, M. H., Zhang, Y., et al. (2014) · Cell Research · doi:10.1038/cr.2014.154 · Cited by 203 · see citing works
Revealing the mechanism behind IL-23 driven autoimmunity
Gyülvészi, G. (2010) · Zurich Open Repository and Archive (University of Zurich) · doi:10.5167/uzh-163957
Fate-Mapping of GM-CSF Expression Identifies a Discrete Subset of Inflammation-Driving T Helper Cells Regulated by Cytokines IL-23 and IL-1β
Komuczki, J., Tuzlak, S., Friebel, E., Hartwig, T., Spath, S., Rosenstiel, P., Waisman, A., Opitz, L., Oukka, M., Schreiner, B., et al. (2019) · Immunity · doi:10.1016/j.immuni.2019.04.006 · Cited by 201 · see citing works
T Cell-Derived GM-CSF, Regulation of Expression and Function
Sheng, W. (2015) · Immunome Research · doi:10.4172/1745-7580.1000098 · Cited by 8 · see citing works

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 › Pathology and Forensic Medicine › 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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