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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
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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“Th2 cells regulate multiple non-immune tissue cells at mucosal sites”
From TH17 cell heterogeneity and its role in tissue inflammation (2023) · cites this paper as [25]
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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 (McQualter et al., 2001; Codarri et al., 2011).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Codarri et al., 2011
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Korn, T., & Kallies, A. (2017) · Nature Reviews Immunology · doi:10.1038/nri.2016.144 · Cited by 268
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
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
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 271
“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.”
BackgroundDual 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 278
Targeting GM-CSF in inflammatory diseases
Wicks, I. P., & Roberts, A. W. (2015) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2015.161 · Cited by 271
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
“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…”
BackgroundMcGinley, 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
“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).”
BackgroundMethodExperimental 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
“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).”
BackgroundInfluentialMicroRNA-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 245
Th17 Response and Inflammatory Autoimmune Diseases
Waite, J. C., & Skokos, D. (2011) · International Journal of Inflammation · doi:10.1155/2012/819467 · Cited by 243
Chemin, K., Gerstner, C., & Malmström, V. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00353 · Cited by 243
“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).”
BackgroundILC3 GM-CSF production and mobilisation orchestrate acute intestinal inflammation
Pearson, C. F., Thornton, E. E., McKenzie, B. S., Schaupp, A.-L., Huskens, N., Griseri, T., West, N. R., Tung, S. L., Seddon, B. P., Uhlig, H. H., et al. (2016) · eLife · doi:10.7554/elife.10066 · Cited by 244
“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).”
BackgroundGM-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 237
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 244
“cytokines inhibit the polarization of GM-CSF–producing cells (9, 10).”
BackgroundResultInfluentialToll-like receptor 4 signaling in T cells promotes autoimmune inflammation
Reynolds, J. M., Martínez, G., Chung, Y., & Dong, C. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1120585109 · Cited by 240
“Recent work has shown that IL-23-driven production of GMCSF by Th17 cells is critical for the development of EAE (23, 24).”
BackgroundNeutrophils 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 234
Peters, A., Lee, Y., & Kuchroo, V. K. (2011) · Current Opinion in Immunology · doi:10.1016/j.coi.2011.08.007 · Cited by 242
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 234
“Proinflammatory cytokines in general and GMCSF in particular are crucial for development of EAE (42).”
BackgroundCardiac 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
“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.”
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
“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).”
BackgroundRoles 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
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
“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).”
BackgroundInfluentialMultiple 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 242
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 225
Wüthrich, M., Deepe, G. S., & Klein, B. S. (2012) · Annual Review of Immunology · doi:10.1146/annurev-immunol-020711-074958 · Cited by 234
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 230
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 235
“…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).”
BackgroundTh17 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 229
“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.”
BackgroundCholesterol 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
“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.”
BackgroundGM-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
“These data suggested that EAE reactive T cells activate the microglial cells through the secretion of GM-CSF (132-134).”
Background
Metadata
- 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
- Venue
- Nature Immunology
- Published
- 2011-04-24
- Volume
- 12
- Issue
- 6
- Pages
- 560-567
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- 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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