Stem-like intestinal Th17 cells give rise to pathogenic effector T cells during autoimmunity
Open accessAbstract
While intestinal Th17 cells are critical for maintaining tissue homeostasis, recent studies have implicated their roles in the development of extra-intestinal autoimmune diseases including multiple sclerosis. However, the mechanisms by which tissue Th17 cells mediate these dichotomous functions remain unknown. Here, we characterized the heterogeneity, plasticity, and migratory phenotypes of tissue Th17 cells in vivo by combined fate mapping with profiling of the transcriptomes and TCR clonotypes of over 84,000 Th17 cells at homeostasis and during CNS autoimmune inflammation. Inter- and intra-organ single-cell analyses revealed a homeostatic, stem-like TCF1+ IL-17+ SLAMF6+ population that traffics to the intestine where it is maintained by the microbiota, providing a ready reservoir for the IL-23-driven generation of encephalitogenic GM-CSF+ IFN-γ+ CXCR6+ T cells. Our study defines a direct in vivo relationship between IL-17+ non-pathogenic and GM-CSF+ and IFN-γ+ pathogenic Th17 populations and provides a mechanism by which homeostatic intestinal Th17 cells direct extra-intestinal autoimmune disease.
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Anti-IL-17 pathway antibodies are effective in treating plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis.
“anti-IL-17 pathway antibodies are effective in the treatment of inflammatory conditions, including plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis”
From TH17 cell heterogeneity and its role in tissue inflammation (2023) · cites this paper as [28]
Th17 cells are implicated in the pathogenesis of multiple autoimmune and inflammatory disorders.
“IL-17-producing CD4+ T cells (Th17 cells) have been implicated in the pathogenesis of multiple autoimmune and inflammatory disorders.”
From TH17 cell heterogeneity and its role in tissue inflammation (2023) · cites this paper as [28]
Selective IL-23 inhibitors (tildrakizumab, risankizumab, guselkumab) targeting IL-23 p19 are more effective than TNF inhibitors and IL-23/IL-12 inhibitors.
“More recently, selective IL-23 inhibitors (tildrakizumab, risankizumab, and guselkumab) that specifically target the IL-23 p19 subunit were found to be more effective than TNF inhibitors [137] and IL-23/IL-12 inhibitors [28, 138].”
From TH17 cell heterogeneity and its role in tissue inflammation (2023) · cites this paper as [28]
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References 100 · Cited by 268
Research works printed but not linked: 3
- COSORICH I, DALLA-COSTA G, SORINI C, FERRARESE R, MESSINA MJ, DOLPADY J, RADICE E, MARIANI A, TESTONI PA, CANDUCCI F, COMI G, MARTINELLI V & FALCONE M 2017. High frequency of intestinal TH17 cells correlates with microbiota alterations and disease activity in multiple sclerosis. Sci Adv, 3, e1700492. 28706993 PMC5507635
- KEBIR H, IFERGAN I, ALVAREZ JI, BERNARD M, POIRIER J, ARBOUR N, DUQUETTE P & PRAT A 2009. Preferential recruitment of interferon-gamma-expressing TH17 cells in multiple sclerosis. Ann Neurol, 66, 390– 402. 19810097
- YU X, ROLLINS D, RUHN KA, STUBBLEFIELD JJ, GREEN CB, KASHIWADA M, ROTHMAN PB, TAKAHASHI JS & HOOPER LV 2013. TH17 cell differentiation is regulated by the circadian clock. Science, 342, 727– 30. 24202171 PMC4165400
- Authors
- 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., Pawlak, M., Meyer zu Horste, G., Rozenblatt-Rosen, O., Irizarry, R. A., Regev, A., & Kuchroo, V. K.
- Affiliations
- Broad Institute (US)
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Regev, Aviv
- Kuchroo, Vijay K.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2021-12
- Volume
- 184
- Issue
- 26
- Pages
- 6281-6298.e23
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC8900676
- OpenAlex
- W4200050535
- Cited by
- 268
- References
- 100
- Citations by year
- 2026: 54 · 2025: 61 · 2024: 69 · 2023: 49 · 2022: 34
- FWCI
- 14.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 386 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Zenodo (CERN European Organization for Nuclear Research) (cc-by)
- Funders
- National Human Genome Research Institute (R01HG005220)
- National Institute of General Medical Sciences (R35GM131802)
- National Institute of Allergy and Infectious Diseases (P01AI073748, U19AI133524, P01AI056299, P01AI039671, R01AI144166)
- National Institute of Neurological Disorders and Stroke (R01NS030843, R01NS045937)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Keywords
- Th17 plasticity, T cell migration, TCF1, SLAMF6, IL-17, GM-CSF, interferon-gamma, CXCR6, IL-23, microbiota, central nervous system autoimmunity, multiple sclerosis, encephalitogenic T cells, TCR clonotypes, single-cell transcriptomics
- MeSH terms
- Signaling Lymphocytic Activation Molecule Family, Receptors, CXCR6, RNA-Seq, Animals, Cell Movement, Clone Cells, Encephalomyelitis, Autoimmune, Experimental, Homeostasis, Humans, Interferon-gamma, Intestines, Mice, Inbred C57BL, Organ Specificity, Receptors, Antigen, T-Cell, RNA, Spleen, Stem Cells, Reproducibility of Results, Autoimmunity, Granulocyte-Macrophage Colony-Stimulating Factor, Receptors, Interleukin, Interleukin-17, Mice, Th17 Cells, Single-Cell Analysis
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