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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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BackgroundFunctional immune cell–astrocyte interactions
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Suryawanshi, A. S., Manoharan, I., Hong, Y., Swafford, D., Majumdar, T., Taketo, M. M., Manicassamy, B., Koni, P. A., Thangaraju, M., Sun, Z., et al. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1402691 · Cited by 127
Natalizumab in Multiple Sclerosis Treatment: From Biological Effects to Immune Monitoring
Khoy, K., Mariotte, D., Defer, G. L., Petit, G., Toutirais, O., & Mauff, B. L. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.549842 · Cited by 140
“In addition, in EAE models, infiltration of Th17 cells or GM-CSF-producing Th1/Th17 cells into the CNS has been shown to be mediated by lymphocyte function associated antigen 1 (LFA1) adhesion molecules and not VLA4 integrin, thereby suggesting more differential effects of anti-VLA4 blockade, at least, in animal model…”
BackgroundZgair, A., Lee, J.-B., Wong, J. C., Taha, D. A., Aram, J., Virgilio, D. D., Mcarthur, J., Cheng, Y.-K., Hennig, I., Barrett, D., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-15026-z · Cited by 117
Dectin-1 isoforms contribute to distinct Th1/Th17 cell activation in mucosal candidiasis
Carvalho, A., Giovannini, G., LUCA, A. D., D'Angelo, C., Casagrande, A., Iannitti, R. G., Ricci, G., Cunha, C., & Romani, L. R. (2012) · Cellular and Molecular Immunology · doi:10.1038/cmi.2012.1 · Cited by 111
Ronchi, F., Basso, C., Preite, S., Reboldi, A., Baumjohann, D., Perlini, L., Lanzavecchia, A., & Sallusto, F. (2016) · Nature Communications · doi:10.1038/ncomms11541 · Cited by 115
A role for G‐CSF and GM‐CSF in nonmyeloid cancers
Aliper, A. M., Korovkina, V. P., Buzdin, A. A., Roumiantsev, S. A., & Zhavoronkov, A. A. (2014) · Cancer Medicine · doi:10.1002/cam4.239 · Cited by 116
“They function to stimulate granulopoiesis, the innate immunity, and the differentiation of neural progenitor cells [1–5].”
BackgroundGM-CSF–Responsive Monocyte-Derived Dendritic Cells Are Pivotal in Th17 Pathogenesis
Ko, H., Brady, J. L., Ryg-Cornejo, V., Hansen, D. S., Vremec, D., Shortman, K., Zhan, Y., & Lew, A. M. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1302040 · Cited by 115
Microglial Phenotypes and Functions in Multiple SclerosisPreprint
O'Loughlin, E. K., Madore, C., Lassmann, H., & Butovsky, O. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a028993 · Cited by 133
“In vivo, GM-CSF was shown to be essential in the induction of encephalitogenic CD4+ T cells in EAE (El-Behi et al. 2011).”
BackgroundWüthrich, M., Deepe, G. S., & Klein, B. S. (2012) · Annual Review of Immunology · doi:10.1146/annurev-immunol-020711-074958 · Cited by 234
Monocyte homeostasis and the plasticity of inflammatory monocytes
Mitchell, A. J., Roediger, B., & Weninger, W. (2014) · Cellular Immunology · doi:10.1016/j.cellimm.2014.05.010 · Cited by 117
Is macrophage polarization important in rheumatoid arthritis?
Wang, Y., Han, C.-C., Cui, D., Li, Y., Ma, Y., & Wei, W. (2017) · International Immunopharmacology · doi:10.1016/j.intimp.2017.07.019 · Cited by 111
IL-17-Producing Cells in Tumor Immunity: Friends or Foes?
Kuen, D., Kim, B., & Chung, Y. (2020) · Immune Network · doi:10.4110/in.2020.20.e6 · Cited by 125
“Other cytokine production, such as IL-17F, IL-21, GM-CSF, and IL-22, has also been associated with Th17, and these effector cytokines allow Ag-specific Th17 cells to be pathogenic in autoimmunity (6-9).”
BackgroundMolecular control of pathogenic Th17 cells in autoimmune diseases
Wu, B., & Wan, Y. Y. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.106187 · Cited by 128
Pathogenic T cell cytokines in multiple sclerosis
Wagner, C. A., Roqué, P. J., & Goverman, J. M. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20190460 · Cited by 132
IL-27 and IL-12 oppose pro-inflammatory IL-23 in CD4+ T cells by inducing Blimp1
Heinemann, C., Heink, S., Petermann, F., Vasanthakumar, A., Rothhammer, V., Doorduijn, E. M., Mitsdoerffer, M., Sie, C., da Costa, O. P., Buch, T., et al. (2014) · Nature Communications · doi:10.1038/ncomms4770 · Cited by 115
Microbiota in autoimmunity and tolerance
Atarashi, K., & Honda, K. (2011) · Current Opinion in Immunology · doi:10.1016/j.coi.2011.11.002 · Cited by 117
Small intestinal eosinophils regulate Th17 cells by producing IL-1 receptor antagonist
Sugawara, R., Lee, E., Jang, M. S., Jeun, E.-J., Hong, C., Kim, J.-H., Park, A., Yun, C. H., Hong, S., Kim, Y., et al. (2016) · The Journal of Experimental Medicine · doi:10.1084/jem.20141388 · Cited by 116
“In addition, Th17 cells activated by IL-1 or IL-23 were reported to produce GM-CSF (El-Behi et al., 2011; Griseri et al., 2012).”
BackgroundCytokine-Defined B Cell Responses as Therapeutic Targets in Multiple Sclerosis
Li, R., Rezk, A., Healy, L. M., Muirhead, G., Prat, A., Gommerman, J. L., & Bar‐Or, A. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00626 · Cited by 107
NAD+ protects against EAE by regulating CD4+ T-cell differentiation
Tullius, S. G., Biefer, H. R. C., Li, S., Trachtenberg, A. J., Edtinger, K., Quante, M., Krenzien, F., Uehara, H., Yang, X., Kissick, H. T., et al. (2014) · Nature Communications · doi:10.1038/ncomms6101 · Cited by 107
Dendritic cell recruitment and activation in autoimmunity
Sozzani, S., Prete, A. D., & Bosisio, D. (2017) · Journal of Autoimmunity · doi:10.1016/j.jaut.2017.07.012 · Cited by 122
RBPJ Controls Development of Pathogenic Th17 Cells by Regulating IL-23 Receptor Expression
zu Hörste, G. M., Wu, C., Wang, C., Cong, L., Pawlak, M., Lee, Y., Elyaman, W., Xiao, S., Regev, A., & Kuchroo, V. K. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.05.088 · Cited by 118
“IL-23R controls the production of a proinflammatory transcriptional module in Th17 cells (Lee et al., 2012), including many essential effector cytokines (Codarri et al., 2011; El-Behi et al., 2011).”
BackgroundAn Update on PYRIN Domain-Containing Pattern Recognition Receptors: From Immunity to Pathology
Ratsimandresy, R. A., Dorfleutner, A., & Stehlik, C. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00440 · Cited by 114
“But this concept has been challenged recently by the discovery that only T helper-derived GM-CSF, and neither IFNγ nor IL-17, was essential during the effector phase of EAE, the animal model for MS (210, 211).”
BackgroundGut-Specific Delivery of T-Helper 17 Cells Reduces Obesity and Insulin Resistance in Mice
Hong, C., Park, A., Yang, B., Yun, C. H., Kwak, M.-J., Lee, G.-W., Kim, J. H., Jang, M. S., Lee, E., Jeun, E.-J., et al. (2017) · Gastroenterology · doi:10.1053/j.gastro.2017.02.016 · Cited by 119
Innate IL-17 and IL-22 responses to enteric bacterial pathogens
Rubino, S. J., Geddes, K., & Girardin, S. E. (2012) · Trends in Immunology · doi:10.1016/j.it.2012.01.003 · Cited by 105
Th17 cells, γδ T cells and their interplay in EAE and multiple sclerosis
McGinley, A. M., Edwards, S. C., Raverdeau, M., & Mills, K. H. G. (2018) · Journal of Autoimmunity · doi:10.1016/j.jaut.2018.01.001 · Cited by 130
Tsai, H., Velichko, S., Hung, L.-Y., & Wu, R. (2013) · Clinical and Developmental Immunology · doi:10.1155/2013/267971 · Cited by 118
The role of Th17 cells in auto-inflammatory neurological disorders
Tahmasebinia, F., & Pourgholaminejad, A. (2017) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.07.023 · Cited by 111
“In the context of CNS autoimmunity, El-Behi et al. indicated that IL-1 and IL-23 induced production of GM-CSF from Th17 cells and that GM-CSF had a vital role in their encephalitogenicity (El-Behi et al. , 2011).”
BackgroundTh17-cell plasticity in Helicobacter hepaticus–induced intestinal inflammation
Morrison, P. J., Bending, D., Fouser, L. A., Wright, J. F., Stockinger, B., Cooke, A., & Kullberg, M. C. (2013) · Mucosal Immunology · doi:10.1038/mi.2013.11 · Cited by 97
“Thus, we found that a large proportion of IFN-g single-positive CD4þ lymphocytes in the inflamed intestine of T-cellsufficient mice were once IL-17Aþ , a finding analogous to that observed in the spinal cord of mice with EAE.17 Hence, together, it is tempting to speculate that IL-17Aþ cells are pathogenic in T-cell-su…”
BackgroundIL-1–induced Bhlhe40 identifies pathogenic T helper cells in a model of autoimmune neuroinflammation
Lin, C., Bradstreet, T. R., Schwarzkopf, E. A., Jarjour, N. N., Chou, C., Archambault, A. S., Sim, J. E., Zinselmeyer, B. H., Carrero, J. A., Wu, G. F., et al. (2016) · The Journal of Experimental Medicine · doi:10.1084/jem.20150568 · Cited by 102
T cell-derived IL-17 mediates epithelial changes in the airway and drives pulmonary neutrophilia
Fogli, L. K., Sundrud, M. S., Goel, S., Bajwa, S., Jensen, K., Derudder, E., Sun, A., Coffre, M., Uyttenhove, C., Snick, J. V., et al. (2013) · Journal of Immunology · doi:10.4049/jimmunol.1301360 · Cited by 103
“This is significant in light of the finding that the capacity of Th17 cells to produce GM-CSF is necessary for Th17-induced inflammation in the inflammatory disease model experimental autoimmune encephalomyelitis (32).”
BackgroundMechanisms and functions of SUMOylation in health and disease: a review focusing on immune cells
Huang, C.-H., Yang, T.-T., & Lin, K. (2024) · Journal of Biomedical Science · doi:10.1186/s12929-024-01003-y · Cited by 109
Xue, G., Jin, G., Fang, J., & Lu, Y. (2019) · Nature Communications · doi:10.1038/s41467-019-09401-9 · Cited by 108
The Properties of Cytokines in Multiple Sclerosis: Pros and Cons
Wang, K., Song, F., Fernandez-Escobar, A., Luo, G., Wang, J., & Sun, Y. S. (2018) · The American Journal of the Medical Sciences · doi:10.1016/j.amjms.2018.08.018 · Cited by 128
The Th17 Lineage: From Barrier Surfaces Homeostasis to Autoimmunity, Cancer, and HIV-1 Pathogenesis
Wacleche, V. S., LANDAY, A. L., Routy, J., & Ancuța, P. (2017) · Viruses · doi:10.3390/v9100303 · Cited by 109
“Pathogenic Th17 cells have been extensively described in the context of autoimmunity as a source of TNF-α and GM-CSF [13,27,83] and were originally discovered in the context of EAE murine models [6,37].”
BackgroundBenveniste, E. N., Liu, Y., McFarland, B. C., & Qin, H. (2014) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2014.0012 · Cited by 117
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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