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The encephalitogenicity of TH17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF
Open accessAbstract
Interleukin 17 (IL-17)-producing helper T cells (T(H)17 cells) require exposure to IL-23 to become encephalitogenic, but the mechanism by which IL-23 promotes their pathogenicity is not known. Here we found that IL-23 induced production of the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) in T(H)17 cells and that GM-CSF had an essential role in their encephalitogenicity. Our findings identify a chief mechanism that underlies the important role of IL-23 in autoimmune diseases. IL-23 induced a positive feedback loop whereby GM-CSF secreted by T(H)17 cells stimulated the production of IL-23 by antigen-presenting cells. Such cross-regulation of IL-23 and GM-CSF explains the similar pattern of resistance to autoimmunity when either of the two cytokines is absent and identifies T(H)17 cells as a crucial source of GM-CSF in autoimmune inflammation.
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“and to promote the production of effector molecules (El-Behi et al., 2011).”
From Distinct characteristics of hippocampal pathogenic th17 cells in a mouse model of depression (2018) · cites this paper as El-Behi et al., 2011
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BackgroundInfluentialIL-17 and GM-CSF Expression Are Antagonistically Regulated by Human T Helper Cells
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BackgroundResultInfluentialExperimental Autoimmune Encephalomyelitis (EAE) as Animal Models of Multiple Sclerosis (MS)
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BackgroundBroughton, 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).”
BackgroundMicroRNA-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
“In fact, Th1 cells that lack the ability to produce GM-CSF do not transfer EAE (42).”
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
“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 Th17 family: flexibility follows function
Basu, R., Hatton, R. D., & Weaver, C. T. (2013) · Immunological Reviews · doi:10.1111/imr.12035 · Cited by 229
“In the thymus, nTregs undergo demethylation of an upstream cis-regulatory element (Foxp3 CNS2) that is bound by Foxp3 in a Runx1- and Cbf-b-dependent manner to establish a positive feedback loop that stabilizes Foxp3 expression.”
BackgroundInfluentialPouring 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
“Additionally, the IL-23R–mediated induction of the cytokine GM-CSF is required for the pathogenicity of Th17 cells, although by itself it is not sufficient to induce EAE in vivo (56, 57).”
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
Fructose and hepatic insulin resistance
Softic, S., Stanhope, K. L., Boucher, J., Divanovic, S., Lanaspa, M. A., Johnson, R. J., & Kahn, C. R. (2020) · Critical Reviews in Clinical Laboratory Sciences · doi:10.1080/10408363.2019.1711360 · Cited by 257
“helper cell polarization and promote skewing of naive CD4þ T cells into Th17 subset [101,102].”
BackgroundCD 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
“El-Behi M, et al. The encephalitogenicity of T(H) 17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF.”
BackgroundInfluentialILC3 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
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 229
“This work was followed by two important studies that identified GM-CSF as an essential factor induced by IL-23 to regulate pathogenic function of Th17 cells (45, 46).”
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.”
BackgroundInfluentialvan 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
“Th17 polyfunctionality is differently regulated between species, as reflected by the antagonistic regulation of IL-17 and GM-CSF expression in human compared to murine T helper cells (El-Behi et al., 2011; Noster et al., 2014; Paterka et al., 2016).”
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
“It was later shown that GM-CSF secreted by Th17 cells is the main cytokine contributing to encephalitogenicity (62).”
BackgroundSelf-citationImmunological mechanisms and therapeutic targets of fatty liver diseases
Wang, H., Mehal, W. Z., Nagy, L. E., & Rotman, Y. (2020) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-00579-3 · Cited by 234
Helminth Immunomodulation in Autoimmune Disease
Smallwood, T. B., Giacomin, P., Loukas, A. C., Mulvenna, J. P., Clark, R. J., & Miles, J. J. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00453 · Cited by 232
Gut Microbiota, Immunity, and Disease: A Complex Relationship
Kosiewicz, M. M., Zirnheld, A. L., & Alard, P. (2011) · Frontiers in Microbiology · doi:10.3389/fmicb.2011.00180 · Cited by 207
“…appears to induce Th17 or RORγt+ T cells to produce GM-CSF that is required for disease induction; this was demonstrated in experiments showing that GM-CSF-producing IL-17-deficient T cells, but not GM-CSF-deficient Th17 cells, were able to induce EAE (Codarri et al., 2011; El-Behi et al., 2011).”
BackgroundInfluentialSheng, 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
Pivotal Roles of GM‐CSF in Autoimmunity and Inflammation
Shiomi, A., & Usui, T. (2015) · Mediators of Inflammation · doi:10.1155/2015/568543 · Cited by 205
Cytokines IL-17 and IL-22 in the host response to infection
Valeri, M., & Raffatellu, M. (2016) · Pathogens and Disease · doi:10.1093/femspd/ftw111 · Cited by 202
“2011 ) and a regulatory subset that produces IL-10 (Esplugues et al.”
BackgroundKomuczki, 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
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 242
Regulation of the T Cell Response by CD39
Takenaka, M. C., Robson, S. C., & Quintana, F. J. (2016) · Trends in Immunology · doi:10.1016/j.it.2016.04.009 · Cited by 211
“GM-CSF, for example, is expressed by pathogenic Th17 cells (74, 75).”
BackgroundGriseri, T., McKenzie, B. S., Schiering, C., & Powrie, F. M. (2012) · Immunity · doi:10.1016/j.immuni.2012.08.025 · Cited by 208
“Indeed, GM-CSF enhances IL-23 production by antigen-presenting cells in vitro (El-Behi et al., 2011).”
BackgroundThe Common Cytokine Receptor γ Chain Family of CytokinesPreprint
Lin, J., & Leonard, W. J. (2017) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a028449 · Cited by 215
“…TGF-β (McGeachy et al. 2007), whereas pathogenic Th17 cells are generated when proinflammatory IL-23 is additionally present, thereby inhibiting Th17 cells from producing IL-10 and up-regulating granulocyte macrophage colony-stimulating factor (GM-CSF) (Codarri et al. 2011; El-Behi et al. 2011).”
BackgroundMyeloid Colony-Stimulating Factors as Regulators of Macrophage Polarization
Hamilton, T. A., Zhao, C., Pavicic, P. G., & Datta, S. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00554 · Cited by 200
“Particularly, T-cell derived GM-CSF was recently shown to be critical for disease phenotype in experimental autoimmune encephalomyelitis, generated by IL-23 action on Th17 cells (60, 61).”
BackgroundCurrent concepts of severe asthma
Ray, A., Raundhal, M. R., Oriss, T. B., Ray, P., & Wenzel, S. E. (2016) · Journal of Clinical Investigation · doi:10.1172/jci84144 · Cited by 208
Akdiş, M., Palomares, Ó., van de Veen, W., van Splunter, M. E., & Akdiş, C. A. (2012) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2012.05.003 · Cited by 201
Cutting Edge: The Pathogenicity of IFN-γ–Producing Th17 Cells Is Independent of T-bet
Duhen, R., Glatigny, S., Arbelaez, C. A., Blair, T. C., Oukka, M., & Bettelli, E. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1203172 · Cited by 176
Bandukwala, H. S., Gagnon, J. D., Togher, S., Greenbaum, J., Lamperti, E. D., Parr, N. J., Molesworth, A. M. H., Smithers, N. N., Lee, K. C., Witherington, J. J., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1212264109 · Cited by 184
“One explanation stems from the fact that this adoptive transfer model has a strong requirement for the cytokine GM-CSF (11, 14) in addition to the well-established proinflammatory cytokines, IFN-γ and IL-17 (20, 21).”
BackgroundResultModeling the heterogeneity of multiple sclerosis in animals
Simmons, S. B., Pierson, E. R., Lee, S. Y., & Goverman, J. M. (2013) · Trends in Immunology · doi:10.1016/j.it.2013.04.006 · Cited by 184
Defining the human T helper 17 cell phenotype
Annunziato, F., Cosmi, L., Liotta, F., Maggi, E., & Romagnani, S. (2012) · Trends in Immunology · doi:10.1016/j.it.2012.05.004 · Cited by 202
Griseri, T., Arnold, I., Pearson, C., Krausgruber, T., Schiering, C., Franchini, F., Schulthess, J., McKenzie, B., Crocker, P., & Powrie, F. (2015) · Immunity · doi:10.1016/j.immuni.2015.07.008 · Cited by 183
“More recently it was shown that IL-23 stimulated Th17 cells to produce GM-CSF, which was pathogenic in EAE although its functional role was not established (El-Behi et al., 2011).”
BackgroundT‐cell trafficking in the central nervous system
Sallusto, F., Impellizzieri, D., Basso, C., Laroni, A., Uccelli, A., Lanzavecchia, A., & Engelhardt, B. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01140.x · Cited by 190
“showed that GM-CSF, which is induced in Th17 cells by IL-23, is the critical pathogenetic factor required in the effector phase of EAE (35, 36).”
BackgroundMechanisms regulating regional localization of inflammation during CNS autoimmunity
Pierson, E. R., Simmons, S. B., Castelli, L., & Goverman, J. M. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01126.x · Cited by 188
“Although RORγt was implicated as an important transcription factor for GM-CSF expression, the presence of RORγt was not essential for GM-CSF production under certain conditions (particularly in vitro) (52, 53).”
BackgroundResultIL ‐17: overview and role in oral immunity and microbiome
Abusleme, L., & Moutsopoulos, N. M. (2016) · Oral Diseases · doi:10.1111/odi.12598 · Cited by 189
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript pathogenic Th17 is dependent on IL-1 and IL-23 and is required for pathogenicity (Codarri et al., 2011, El-Behi et al., 2011).”
Lin, C., Bradstreet, T. R., Schwarzkopf, E. A., Sim, J. E., Carrero, J. A., Chou, C., Cook, L. E., Egawa, T., Taneja, R., MURPHY, K. M. M., et al. (2014) · Nature Communications · doi:10.1038/ncomms4551 · Cited by 181
Chong, W. P., Mattapallil, M. J., Raychaudhuri, K., Bing, S. J., Wu, S., Zhong, Y., Wang, W., Chen, Z., Silver, P. B., Jittayasothorn, Y., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.06.022 · Cited by 191
Human Th17 Cells Express High Levels of Enzymatically Active Dipeptidylpeptidase IV (CD26)
Bengsch, B., Seigel, B., Flecken, T., Wolanski, J., Blum, H. E., & Thimme, R. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1103801 · Cited by 171
“Indeed, neutralization of IL-17 was inefficient in avoiding Th17-cell mediated disease (29), and several studies suggest that other cytokines produced by Th17 cells, such as GM-CSF, may be more critically involved in inflammation compared with IL-17 (30, 31).”
Background
Metadata
- Authors
- El-Behi, M., Ciric, B., Dai, H., Yan, Y., Cullimore, M., Safavi, F., Zhang, G.-X., Dittel, B. N., & Rostami, A.
- Affiliations
- Thomas Jefferson University (US)
- Versiti Blood Center of Wisconsin (US)
- Corresponding author
- Rostami, Abdolmohamad
- ORCID
- Venue
- Nature Immunology
- Published
- 2011-04-24
- Volume
- 12
- Issue
- 6
- Pages
- 568-575
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC3116521
- OpenAlex
- W2084388036
- Cited by
- 1,071
- References
- 44
- Citations by year
- 2026: 25 · 2025: 38 · 2024: 38 · 2023: 58 · 2022: 62 · 2021: 72 · 2020: 82 · 2019: 71 · 2018: 74 · 2017: 96 · 2016: 82 · 2015: 108 · 2014: 91 · 2013: 80 · 2012: 73
- FWCI
- 37.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Multiple Sclerosis Society
- Mary E. Groff Surgical and Medical Research and Education Charitable Trust
- National Institute of Neurological Disorders and Stroke (R01NS046782)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Keywords
- Th17 cells, experimental autoimmune encephalomyelitis, IL-23, GM-CSF, interleukin-1, encephalitogenicity, autoimmune disease, antigen-presenting cells, positive feedback loop, T helper cells
- MeSH terms
- Animals, Antibodies, Cells, Cultured, Encephalomyelitis, Autoimmune, Experimental, Female, Flow Cytometry, Glycoproteins, Interleukin-1, Mice, Inbred C57BL, Mice, Transgenic, Peptide Fragments, CD4-Positive T-Lymphocytes, Granulocyte-Macrophage Colony-Stimulating Factor, Transforming Growth Factor beta, Mice, Knockout, Th1 Cells, Coculture Techniques, CD11c Antigen, Mice, Interleukin-1beta, Interleukin-23, Nuclear Receptor Subfamily 1, Group F, Member 3, Th17 Cells, Myelin-Oligodendrocyte Glycoprotein
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