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Cited by 286Psoriasis: Treatment and PathogenesisT-cell and B-cell ImmunologyIL-33, ST2, and ILC Pathways

TH17 cell heterogeneity and its role in tissue inflammation

Open access
Schnell, Alexandra, Littman, Dan R., Kuchroo, Vijay K.·2023·Nature Immunology
DOI 10.1038/s41590-022-01387-9PMC PMC10795475
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Abstract

Kuchroo and colleagues review T_H17 cell heterogeneity and discuss how this affects the function of T_H17 cells in homeostasis and disease. Since their discovery almost two decades ago, interleukin-17-producing CD4^+ T cells (T_H17 cells) have been implicated in the pathogenesis of multiple autoimmune and inflammatory disorders. In addition, T_H17 cells have been found to play an important role in tissue homeostasis, especially in the intestinal mucosa. Recently, the use of single-cell technologies, along with fate mapping and various mutant mouse models, has led to substantial progress in the understanding of T_H17 cell heterogeneity in tissues and of T_H17 cell plasticity leading to alternative T cell states and differing functions. In this Review, we discuss the heterogeneity of T_H17 cells and the role of this heterogeneity in diverse functions of T_H17 cells from homeostasis to tissue inflammation. In addition, we discuss T_H17 cell plasticity and its incorporation into the current understanding of T cell subsets and alternative views on the role of T_H17 cells in autoimmune and inflammatory diseases.

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Crossref · 10.1038/s41590-022-01387-9

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  • Findingcitation

    Predicted regulators of the non-pathogenic and general Th17 program include RORγt, ETS1, BACH2, FOSL2, and RBPJ.

    “Predicted regulators of the non-pathogenic- and general- Th17 program included RORγt, ETS1, BACH2, FOSL2, and RBPJ.”
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    • cites [60] Hang, S. et al. Bile acid metabolites control TH17 and Treg cell differentiation. Nature 576, 143–148 (2019). source

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  • Findingcitation

    Integrating single-cell ATAC-seq and single-cell RNA-seq generated a regulatory network across non-pathogenic Th17, pathogenic Th17, and Th1 cells.

    “by integrating single-cell ATAC-seq and single-cell RNA-seq, we generated a regulatory network across npTh17, pTh17, and Th1 cells”
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    • cites [60] Hang, S. et al. Bile acid metabolites control TH17 and Treg cell differentiation. Nature 576, 143–148 (2019). source

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  • Findingown data

    The network predicted that the pathogenic Th17 and Th1 program is regulated by ATF3, BHLHE40, FOS, NR4A1, EOMES, and T-BET.

    “The network predicted the pathogenic Th17- and Th1- program to be regulated by the transcription factors ATF3, BHLHE40, FOS, NR4A1, EOMES, and T-BET.”
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    • cites [60] Hang, S. et al. Bile acid metabolites control TH17 and Treg cell differentiation. Nature 576, 143–148 (2019). source

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  • Findingcitation

    IL-17A/F double-deficient mice are highly resistant to EAE development.

    “when using genetically deficient IL-17A and IL-17F mice, our own unpublished studies and those of others have shown that IL-17A/F double-deficient mice were highly resistant to the development of EAE”
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    • cites [116] Hueber, W. et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci. Transl. Med. 2, 52ra72 (2010). source

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  • Findingcitation

    Profiling Th17 cells from multiple tissues of naïve IL-17-fate reporter mice by single-cell RNA-seq generated an atlas of Th17 diversity.

    “we profiled Th17 cells from multiple tissues of naïve IL-17-fate reporter mice by single-cell RNA-seq”
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    • cites [38] Thakore, P. I. et al. The chromatin landscape of Th17 cells reveals mechanisms of diversification of regulatory and pro-inflammatory states. Preprint at bioRxiv https://doi.org/10.1101/2022.02.26.482041 (2022). source

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    Findingown data

    BACH2 was validated as a regulator of Th17 pathogenicity that promotes immunomodulatory programs and restrains pro-inflammatory Th1-like programs.

    “We validated BACH2 as a novel regulator of Th17 pathogenicity that promoted immunomodulatory programs and restrained pro-inflammatory Th1-like programs in Th17 cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Hang, S. et al. Bile acid metabolites control TH17 and Treg cell differentiation. Nature 576, 143–148 (2019). source

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    Findingcitation

    Blocking the polyamine pathway by perturbing ODC1 or SAT1 alleviates EAE and remodels the transcriptome and epigenome toward a Treg-like program.

    “Blockade of the polyamine pathway by perturbation of ornithine decarboxylase 1 (ODC1) or spermidine/spermine N1 acetyltransferase 1 (SAT1), rate-limiting enzymes of biosynthesis and catabolism in the polyamine pathway, respectively, alleviated EAE disease.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Kullberg, M. C. et al. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J. Exp. Med. 203, 2485–2494 (2006). source

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    Findingown data

    Th17-like Treg clusters are clonally distinct from non-Treg Th17 clusters, indicating that at homeostasis they likely derive from other Treg cells or naïve CD4+ T cells rather than from Th17 cells.

    “Using TCR clonality analysis, the Th17-like Treg clusters were found to be clonally distinct from those of non-Treg Th17 clusters, indicating that, at homeostasis, Th17-like Treg cells likely differentiate from other Treg cells or naïve CD4+ T cells, and not from Th17 cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Thakore, P. I. et al. The chromatin landscape of Th17 cells reveals mechanisms of diversification of regulatory and pro-inflammatory states. Preprint at bioRxiv https://doi.org/10.1101/2022.02.26.482041 (2022). source

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    Findingcitation

    Tissue Th17 cells are highly clonally related within a tissue, suggesting intra-tissue plasticity and transitions between subpopulations.

    “tissue Th17 cells were highly clonally related within a tissue, suggesting intra-tissue plasticity and transitions between subpopulations”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Thakore, P. I. et al. The chromatin landscape of Th17 cells reveals mechanisms of diversification of regulatory and pro-inflammatory states. Preprint at bioRxiv https://doi.org/10.1101/2022.02.26.482041 (2022). source

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    Findingown data

    IL-17A/F-deficient MOG-TCR transgenic 2D2 cells failed to induce disease in Rag1-deficient recipient mice, whereas wildtype 2D2 T cells induced severe disease.

    “we found that IL-17A/F-deficient MOG-TCR transgenic 2D2 cells lacked the ability to induce disease in Rag1-deficient recipient mice, whereas 2D2 T cells from wildtype mice induced severe disease”
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    Findingcitation

    Compass analysis identified polyamine metabolism as a major regulator of T helper cell fate, epigenetic programming, and pathogenic potential, with pathogenic Th17 cells showing increased glycolysis and polyamine biosynthesis and non-pathogenic cells showing enhanced FAO.

    “Using Compass analysis, polyamine metabolism was identified as a major regulator of T helper cell fate direction, epigenetic programming, and pathogenic potential.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Kullberg, M. C. et al. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J. Exp. Med. 203, 2485–2494 (2006). source

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    Findingcitation

    Tfh-like, effector-like, stem-like, proliferating, ISG-expressing, and Treg clusters were identified among tissue Th17 cells.

    “Tfh-like clusters, effector-like clusters, stem-like clusters, proliferating clusters, interferon-stimulated genes (ISGs)-expressing clusters and Treg clusters were identified”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Thakore, P. I. et al. The chromatin landscape of Th17 cells reveals mechanisms of diversification of regulatory and pro-inflammatory states. Preprint at bioRxiv https://doi.org/10.1101/2022.02.26.482041 (2022). source

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    Findingown data

    Spleen and lymphoid Th17 signatures include stem-like genes such as Tcf7, Il7r, and Ccr7, while intestinal tissues upregulate activation genes such as Cd44, Cd69, and Il17a.

    “Tissue Th17 signatures in the spleen and lymphoid tissues included genes associated with a stem-like T-cell state (Tcf7, Il7r, Ccr7 etc.), whereas genes associated with activation of Th17 cells (Cd44, Cd69, Il17a etc.) were upregulated in intestinal tissues.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Thakore, P. I. et al. The chromatin landscape of Th17 cells reveals mechanisms of diversification of regulatory and pro-inflammatory states. Preprint at bioRxiv https://doi.org/10.1101/2022.02.26.482041 (2022). source

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    Findingown data

    Within each tissue, Th17 cells form distinct functional clusters that are transcriptionally similar across tissues, indicating similar Th17 heterogeneity in different tissue sites.

    “Analysis of the variation among Th17 cells within each tissue revealed distinct functional clusters of Th17 cells that, interestingly, were transcriptionally similar to clusters in other tissues, indicating the presence of similar Th17 heterogeneity even in different tissue sites.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Thakore, P. I. et al. The chromatin landscape of Th17 cells reveals mechanisms of diversification of regulatory and pro-inflammatory states. Preprint at bioRxiv https://doi.org/10.1101/2022.02.26.482041 (2022). source

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    Findingown data

    IL-23 signaling in Th1 cells is critical for their ability to become colitogenic, with upregulation of several effector molecules that are not induced by IL-23 in Th17 cells.

    “IL-23 signaling in Th1 cells is critical for their ability to become colitogenic, with upregulation of several effector molecules that are not induced by IL-23 in Th17 cells.”
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    Findingcitation

    A small fraction of Th1 cells express IL-23R, and when differentiated with IL-12 and IL-21, Th1 cells express IL-23R.

    “In a recent study, we found a small fraction of Th1 cells to express IL-23R. When differentiated with IL-12 and IL-21, Th1 cells express IL-23R [173].”
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    • cites [173]

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    Findingown data

    In the 2D2 T cell transfer EAE model, Csf2−/− 2D2 cells transfer similar disease to wildtype 2D2 cells, whereas deletion of Bhlhe40 leads to complete loss of disease.

    “However, in the 2D2 T cell transfer EAE model, Csf2−/− 2D2 cells transfer similar disease to wildtype 2D2 cells, whereas deletion of Bhlhe40 (required for expression of Csf2) leads to complete loss of disease (unpublished).”
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    Findingown data

    In the CNS, the pathogenic CXCR6 population gives rise to multiple different, clonally related Th17 subpopulations, including quiescent, migratory, proliferating, proinflammatory, and CD8-like cells, revealing intra-tissue plasticity and/or transitions.

    “In the CNS, the pathogenic CXCR6 population gives rise to multiple different, clonally related Th17 subpopulations, including quiescent-, migratory-, proliferating-, proinflammatory- and CD8-like cells, revealing intra-tissue plasticity and/or transitions between subpopulations of Th17 cells.”
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    Findingcitation

    Our recent in vivo fate-mapping studies show that in EAE there is significant TCR clonal sharing between homeostatic IL-17A/F+ Th17 cells (SLAMF6+) and pathogenic GM-CSF+ cells (CXCR6+), and there was in vivo conversion of SLAMF6+ cells to CXCR6+ cells upon adoptive transfer, suggesting that pathogenic Th17 cells arise by conversion of homeostatic Th17 cells.

    “Moreover, our recent in vivo fate-mapping studies show that in EAE there is significant TCR clonal sharing between homeostatic IL-17A/F+ Th17 cells (SLAMF6+) and pathogenic GM-CSF+ cells (CXCR6+). There was also in vivo conversion of SLAMF6+ cells to CXCR6+ cells upon adoptive transfer, suggesting that, during EAE, pathogenic Th17 cells arise by the conversion of homeostatic Th17 cells to pathogen”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Thakore, P. I. et al. The chromatin landscape of Th17 cells reveals mechanisms of diversification of regulatory and pro-inflammatory states. Preprint at bioRxiv https://doi.org/10.1101/2022.02.26.482041 (2022). source

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    Findingcitation

    Our recent study combined fate-mapping with single-cell profiling of transcriptomes and TCR clonotypes of Th17 cells during EAE and identified a homeostatic, stem-like TCF1+ IL-17+ SLAMF6+ Th17 cell population that traffics to the intestine where it is maintained by the microbiota.

    “In our recent study we combined fate-mapping with single-cell profiling of the transcriptomes and TCR clonotypes of Th17 cells during EAE and identified a homeostatic, stem-like TCF1+ IL-17+ SLAMF6+ Th17 cell population that traffics to the intestine where it is maintained by the microbiota [38].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Thakore, P. I. et al. The chromatin landscape of Th17 cells reveals mechanisms of diversification of regulatory and pro-inflammatory states. Preprint at bioRxiv https://doi.org/10.1101/2022.02.26.482041 (2022). source

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    Findingown data

    This intestinal SLAMF6+ population shares TCRs with encephalitogenic GM-CSF+ IFNγ+ CXCR6+ T cells, suggesting it may provide a reservoir for the IL-23-driven generation of pathogenic cells.

    “Interestingly, this intestinal SLAMF6+ population shares TCRs with encephalitogenic GM-CSF+ IFNγ+ CXCR6+ T cells, suggesting that it may provide a reservoir for the IL-23-driven generation of the pathogenic cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Thakore, P. I. et al. The chromatin landscape of Th17 cells reveals mechanisms of diversification of regulatory and pro-inflammatory states. Preprint at bioRxiv https://doi.org/10.1101/2022.02.26.482041 (2022). source

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    Premisecitation

    Secukinumab reduces new MRI lesions, cumulative lesion load, and EDSS scores in multiple sclerosis patients.

    “secukinumab was also effective in reducing new magnetic resonance imaging (MRI) lesions, cumulative lesion load, and expanded disability status scale (EDSS) scores in multiple sclerosis (MS) patients”
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    • cites [29] Ghoreschi, K. et al. Generation of pathogenic TH17 cells in the absence of TGF-β signaling. Nature 467, 967–971 (2010). source

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    • cites [30] McGeachy, M. J. et al. TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell-mediated pathology. Nat. Immunol. 8, 1390–1397 (2007). source

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    Premisecitation

    RORγt is expressed in a subset of intestinal CD4+ T cells and is required for IL-17 expression by these cells and by in vitro differentiated Th17 cells.

    “Discovery that the orphan nuclear receptor RORγt was expressed in a subset of intestinal CD4+ T cells and that it was required for expression of IL-17 by both these cells and in vitro differentiated Th17 cells”
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    • cites [16] Vazquez, M. I., Catalan-Dibene, J. & Zlotnik, A. B cells responses and cytokine production are regulated by their immune microenvironment. Cytokine 74, 318–326 (2015). source

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    Premisecitation

    RORγt is necessary and sufficient for at least part of the Th17 gene expression program.

    “Although RORγt was both necessary and sufficient for at least part of the Th17 gene expression program”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Vazquez, M. I., Catalan-Dibene, J. & Zlotnik, A. B cells responses and cytokine production are regulated by their immune microenvironment. Cytokine 74, 318–326 (2015). source

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    Premisecitation

    Th17 cells may contribute to high-affinity IgA production and to IgG2a and IgG3 class switching.

    “Th17 cells may contribute to production of high-affinity IgA antibodies and to IgG2a and IgG3 class switching”
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    • cites [26] Galli, E. et al. GM-CSF and CXCR4 define a T helper cell signature in multiple sclerosis. Nat. Med. 25, 1290–1300 (2019). source

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    • cites [27] Stockinger, B. & Omenetti, S. The dichotomous nature of T helper 17 cells. Nat. Rev. Immunol. 17, 535–544 (2017). source

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    Premisecitation

    Th17 cells mediate tissue homeostasis by protecting mucosal barriers, influencing commensal microbiota, and modulating epithelial permeability.

    “Th17 cells, besides being highly pathogenic and able to induce autoimmunity, have also been implicated in mediating tissue homeostasis, regulating tissue integrity by protecting mucosal barriers from potentially invasive microbes”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [44] Ma, C. S. et al. Deficiency of TH17 cells in hyper IgE syndrome due to mutations in STAT3. J. Exp. Med. 205, 1551–1557 (2008). source

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    • cites [45] Weaver, C. T. et al. The TH17 pathway and inflammatory diseases of the intestines, lungs, and skin. Annu. Rev. Pathol. 8, 477–512 (2013). source

      Not checked in the free run.

    • cites [46] Honda, K. & Littman, D. R. The microbiota in adaptive immune homeostasis and disease. Nature 535, 75–84 (2016). source

      Not checked in the free run.

    • cites [47] Ivanov, I. I. et al. Induction of intestinal TH17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009). This study shows the specific induction of intestinal TH17 cells by SFB. source

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    • cites [48] Atarashi, K. et al. TH17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell 163, 367–380 (2015). source

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    Interpretationreasoning

    The homeostatic function of Th17 cells likely explains why IL-17 blockade in Crohn's disease is ineffective and can worsen colitis.

    “This homeostatic function of Th17 cells likely underlies the finding that blockade of IL-17 in Crohn’s disease is not only ineffective but can exacerbate colitis”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [28] Schnell, A. et al. Stem-like intestinal TH17 cells give rise to pathogenic effector T cells during autoimmunity. Cell 184, 6281–6298 (2021). Analysis of combined single-cell RNA sequencing and T cell receptor sequencing of tissue TH17 cells during homeostasis and EAE, identifying a stem-like intestinal TH17 population that gives rise to pathogenic effector TH17 cells. source

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    • cites [49] Ladinsky, M. S. et al. Endocytosis of commensal antigens by intestinal epithelial cells regulates mucosal T cell homeostasis. Science 363, eaat4042 (2019). source

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    Premisecitation

    IL-23 does not induce Th17 differentiation; it acts on already differentiated Th17 cells to stabilize their effector functions.

    “IL-23 was not the differentiating factor that induces Th17 cells and instead acts on previously differentiated Th17 cells, stabilizing their effector functions”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133–1141 (2005). source

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    Premisecitation

    SFB-induced Th17 cells distribute throughout the intestine, but IL-17 production is largely confined to ileal Th17 cells, partly in response to SAA1/2.

    “These Th17 cells distributed throughout the length of the intestine, but IL-17 cytokine production was largely confined to ileal Th17 cells, in part in response to epithelium-derived serum amyloid A proteins 1 and 2 (SAA1/2)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Komiyama, Y. et al. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol. 177, 566–573 (2006). source

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    Premisecitation

    Regulatory network construction confirmed RORγt's central role in differentiating Th17 cells and identified novel regulators forming mutually antagonistic modules.

    “regulatory networks for Th17 cells were constructed, which confirmed the central role of RORγt in differentiating Th17 cells”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [20] Zwicky, P., Unger, S. & Becher, B. Targeting interleukin-17 in chronic inflammatory disease: a clinical perspective. J. Exp. Med. 217, e20131123 (2020). source

      Not checked in the free run.

    • cites [59] Wang, C. et al. CD5L/AIM regulates lipid biosynthesis and restrains TH17 cell pathogenicity. Cell 163, 1413–1427 (2015). source

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    Premisecitation

    SFB-induced homeostatic Th17 cells have a resting aerobic profile dependent on OXPHOS and can differentiate despite reduced glycolytic flux.

    “Intestinal SFB-induced homeostatic Th17 cells are characterized by a resting aerobic profile primarily dependent on OXPHOS metabolism”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [42] Okada, S. et al. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations. Science 349, 606–613 (2015). source

      Not checked in the free run.

    • cites [94] Li, J., Casanova, J. L. & Puel, A. Mucocutaneous IL-17 immunity in mice and humans: host defense vs. excessive inflammation. Mucosal Immunol. 11, 581–589 (2018). source

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    Premisecitation

    Non-pathogenic and pathogenic Th17 cells have distinct transcriptional signatures: non-pathogenic cells express Il10, Il9, Maf, and Ahr, while pathogenic cells express Csf2, Ifng, Tbx21, Il23r, and Gzmb.

    “non-pathogenic Th17 cells additionally expressed the immunoregulatory genes Il10, Il9, Maf, and Ahr, whereas pathogenic Th17 cells were characterized by the expression of proinflammatory genes including Csf2 (gene encoding GM-CSF), Ifng, Tbx21, Il23r and Gzmb”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [53] Chudnovskiy, A. et al. Host–protozoan interactions protect from mucosal infections through activation of the inflammasome. Cell 167, 444–456.e14 (2016). source

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    • cites [54] Wu, C. et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496, 513–517 (2013). source

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    Premisecitation

    Human Th17 memory cells specific for C. albicans produce IL-17 and IFNγ but no IL-10, resembling pathogenic Th17 cells.

    “Th17 memory cells (initially defined as CCR4+CCR6+) specific for Candida albicans (C. albicans) produced IL-17 and IFNγ and no IL-10, and thus resemble pathogenic Th17 cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Puleston, D. J. et al. Polyamine metabolism is a central determinant of helper T cell lineage fidelity. Cell 184, 4186–4202.e20 (2021). source

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    Premisecitation

    SFB induction of Th17 cells in the small intestine does not cause a proinflammatory reaction but induces a homeostatic population that supports barrier function.

    “the induction of Th17 cells by SFB in the small intestine does not induce a proinflammatory reaction in the intestine, but instead induces a homeostatic Th17 population that supports intestinal barrier function”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [37] Yosef, N. et al. Dynamic regulatory network controlling TH17 cell differentiation. Nature 496, 461–468 (2013). source

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    • cites [43] Puel, A. et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 332, 65–68 (2011). source

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    Premisecitation

    The secondary bile acids 3-oxo-LCA and iso-LCA inhibit intestinal Th17 differentiation by binding RORγt, while isoalloLCA enhances intestinal Treg differentiation.

    “the secondary bile acids 3-oxo-lithocholic acid (LCA) and iso-LCA inhibit the differentiation of intestinal Th17 cells by direct binding to RORγt, isoalloLCA enhances the differentiation of intestinal Treg cells”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Izcue, A. et al. Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. Immunity 28, 559–570 (2008). source

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    Premisecitation

    A high-salt diet increases intestinal Th17 cell numbers and exacerbates Th17-dependent autoimmunity.

    “A high-salt diet increases the number of Th17 cells in the intestine and exacerbates Th17-dependent autoimmunity”
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    • cites [84] Cai, Y. et al. Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation. Immunity 35, 596–610 (2011). source

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    • cites [85] Pantelyushin, S. et al. Rorγt+ innate lymphocytes and γδ T cells initiate psoriasiform plaque formation in mice. J. Clin. Invest. 122, 2252–2256 (2012). source

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    Premisecitation

    CD5L is selectively expressed by non-pathogenic in vitro Th17 cells and inhibits their acquisition of a pathogenic phenotype.

    “CD5 antigen-like (CD5L), a regulator of lipid metabolism, was selectively expressed by Th17 cells differentiated in vitro under non-pathogenic conditions, and was shown to inhibit Th17 cells to attain a pathogenic Th17 cell phenotype”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Kawano, Y. et al. Microbiota imbalance induced by dietary sugar disrupts immune-mediated protection from metabolic syndrome. Cell 185, 3501–3519.e20 (2022). source

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    Premisecitation

    At homeostasis, Th17 cells are the main source of IL-17A, while ILC3s are the main source of IL-22.

    “Transcriptomic and fate-mapping studies indicate that at homeostasis the main source of IL-17A is Th17 cells, while most IL-22 is derived from ILC3s”
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    • cites [76] Yang, X. O. et al. Regulation of inflammatory responses by IL-17F. J. Exp. Med. 205, 1063–1075 (2008). source

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    • cites [77] Hofstetter, H. H. et al. Therapeutic efficacy of IL-17 neutralization in murine experimental autoimmune encephalomyelitis. Cell Immunol. 237, 123–130 (2005). source

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    Premisecitation

    CXCR3+CCR6+ Th1* cells resemble pathogenic Th17 cells and are required to control C. albicans and mycobacteria, including BCG.

    “the CXCR3+CCR6+ cells, named Th1* cells, resemble pathogenic Th17 cells and are required to control infection with both C. albicans and mycobacteria, including the attenuated Bacillus Calmette-Guerin (BCG)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [64] Karmaus, P. W. F. et al. Metabolic heterogeneity underlies reciprocal fates of TH17 cell stemness and plasticity. Nature 565, 101–105 (2019). source

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    • cites [67] Shi, L. Z. et al. HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med. 208, 1367–1376 (2011). source

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    Premisecitation

    High salt induces SGK1, which deactivates FOXO1 and promotes IL-23R expression and pathogenic Th17 generation.

    “The increase in salt concentration induces the expression of serum/glucocorticoid-regulated kinase 1 (SGK1) that deactivates FOXO1 and thereby promotes the expression of IL-23R and the generation of pathogenic Th17 cells”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Cai, Y. et al. Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation. Immunity 35, 596–610 (2011). source

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  • May combine two claims.

    Interpretationcitation

    In humans, BACH2 might regulate homeostatic Th17 cells and could be exploited to treat autoimmune diseases.

    “Hence, in humans BACH2 might be an important regulator of homeostatic Th17 cells that could be exploited for the treatment of human autoimmune diseases.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [60] Hang, S. et al. Bile acid metabolites control TH17 and Treg cell differentiation. Nature 576, 143–148 (2019). source

      Not checked in the free run.

    • cites [62] Chen, M. L. et al. CAR directs T cell adaptation to bile acids in the small intestine. Nature 593, 147–151 (2021). source

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  • May combine two claims.

    Premisecitation

    IL-17A, IL-17F, and IL-22 induce antimicrobial proteins and tight junction formation in intestinal epithelial cells and are implicated in regulating IgA responses.

    “The Th17 cell-signature cytokines IL-17A, IL-17F, and IL-22 induce the expression of antimicrobial proteins and the formation of tight junctions by intestinal epithelial cells and have been implicated in regulation of IgA responses”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [70] Gribonika, I. et al. Peyer’s patch TH17 cells are dispensable for gut IgA responses to oral immunization. Sci. Immunol. 7, eabc5500 (2022). source

      Not checked in the free run.

    • cites [71] Gagliani, N. et al. TH17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 523, 221–225 (2015). source

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  • May combine two claims.

    Premisecitation

    IL-6, IL-1β, and IL-23 or IL-6, TGF-β, and IL-23 generate pathogenic Th17 cells that are highly potent in transferring disease.

    “IL-6, IL-1ß and IL-23 or IL-6, TGF-ß, and IL-23 differentiate Th17 cells that are highly potent in transferring disease (pathogenic Th17 cells)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [39] Zielinski, C. E. et al. Pathogen-induced human TH17 cells produce IFN-γ or IL-10 and are regulated by IL-1β. Nature 484, 514–518 (2012). source

      Not checked in the free run.

    • cites [53] Chudnovskiy, A. et al. Host–protozoan interactions protect from mucosal infections through activation of the inflammasome. Cell 167, 444–456.e14 (2016). source

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  • May combine two claims.

    Premisecitation

    S. aureus-specific Th17 cells produce IL-17 and IL-10 but no IFNγ, resembling non-pathogenic/homeostatic Th17 cells.

    “Staphylococcus aureus (S. aureus)-specific Th17 cells produced IL-17 and IL-10, but no IFNγ, and thus resemble non-pathogenic/homeostatic Th17 cells”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Puleston, D. J. et al. Polyamine metabolism is a central determinant of helper T cell lineage fidelity. Cell 184, 4186–4202.e20 (2021). source

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  • May combine two claims.

    Premisecitation

    Adhesion to the epithelium is thought to be essential for Th17 induction, because rat-derived SFB that does not adhere to mouse small intestinal epithelium fails to induce intestinal Th17 cells.

    “Adhesion to the epithelium is thought to be essential for the induction of Th17 cells, as rat-derived SFB, that does not adhere to the small intestinal epithelium in mouse hosts, failed to induce intestinal Th17 cells”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Munoz-Rojas, A. R. & Mathis, D. Tissue regulatory T cells: regulatory chameleons. Nat. Rev. Immunol. 21, 597–611 (2021). source

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  • May combine two claims.

    Premisecitation

    During C. rodentium infection, early defense is mediated by ILC3-derived IL-22, but protection from systemic dissemination and survival require T-cell-derived IL-22.

    “during C. rodentium infection, while early phase defense is mediated by ILC3-derived IL-22, protection from systemic dissemination and survival require IL-22 production by T cells”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Bettelli, E. et al. Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis. J. Exp. Med. 197, 1073–1081 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Multiple SNPs in the BACH2 locus are associated with human autoimmune diseases, and a protective MS allele correlates with increased BACH2 expression in CD4+ T cells.

    “multiple single-nucleotide polymorphisms (SNPs) in the BACH2 locus are associated with human autoimmune diseases and a protective allele for MS disease correlates with an increase of BACH2 expression in CD4+ T cells”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [60] Hang, S. et al. Bile acid metabolites control TH17 and Treg cell differentiation. Nature 576, 143–148 (2019). source

      Not checked in the free run.

    • cites [62] Chen, M. L. et al. CAR directs T cell adaptation to bile acids in the small intestine. Nature 593, 147–151 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Th17 cells use ACC1-mediated de novo fatty acid synthesis for membrane phospholipids, and ACC1 deletion inhibits Th17-driven autoimmune disease in mice.

    “Th17 cells utilize acetyl-CoA carboxylase 1 (ACC1)-mediated de novo fatty acid synthesis to synthesize phospholipids for cellular membranes”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Noguchi, D. et al. Blocking of IL-6 signaling pathway prevents CD4+ T cell-mediated colitis in a TH17-independent manner. Int. Immunol. 19, 1431–1440 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    CAR detoxifies bile acids and prevents small intestinal inflammation, leading to induction of nonpathogenic/homeostatic Th17 cells.

    “These data suggest a direct role of CAR in detoxifying bile acids and preventing inflammation in the small intestine, resulting in the induction of nonpathogenic/homeostatic Th17 cells”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93] O’Connor, W. Jr. et al. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat. Immunol. 10, 603–609 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Long-chain fatty acids promote Th17 differentiation and worsen EAE, whereas dietary short-chain fatty acids induce intestinal Treg cells and ameliorate EAE.

    “Long-chain fatty acids (LCFAs) promote the differentiation of Th17 cells and enhance the severity of EAE, whereas dietary short-chain fatty acids (SCFAs) induce intestinal Treg cells and ameliorate EAE”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [88] Lubberts, E. IL-17/TH17 targeting: on the road to prevent chronic destructive arthritis? Cytokine 41, 84–91 (2008). source

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  • May combine two claims.

    Premisecitation

    HIF1α is required for Th17 differentiation and mediates glycolysis and FOXP3 degradation, preventing Treg differentiation.

    “The transcription factor hypoxia-inducible factor 1α (HIF1α) plays an essential role in the response to hypoxia and is required for the differentiation of Th17 cells”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [99] Teunissen, M. B. et al. Interleukin-17 and interferon-γ synergize in the enhancement of proinflammatory cytokine production by human keratinocytes. J. Invest. Dermatol. 111, 645–649 (1998). source

      Not checked in the free run.

    • cites [100] Fotiadou, C. et al. IL-17A, IL-22, and IL-23 as markers of psoriasis activity: a cross-sectional, hospital-based study. J. Cutan. Med. Surg. 19, 555–560 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cold exposure ameliorates EAE neuroinflammation with decreased CNS Th17 frequencies, likely through reduced monocyte priming.

    “cold exposure was found to lead to ameliorated neuroinflammation in EAE with decreased frequencies of Th17 cells in the CNS, likely due to reduced priming by monocytes”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] Reich, K. et al. Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials. Lancet 390, 276–288 (2017). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    In IL-17A/F-knockout mice, overexpression of IL-17A by intestinal epithelial cells restored EAE susceptibility, and T cell production of IL-17 was not required for EAE development.

    “In the study they showed that overexpression of IL-17A by intestinal epithelial cells was sufficient to reestablish EAE susceptibility in IL-17A/F-knockout mice and therefore IL-17 production by T cells was not pre-requisite for the development of EAE.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [116] Hueber, W. et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci. Transl. Med. 2, 52ra72 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dermal γδ T cells respond to IL-23 and are a major source of IL-17A, IL-17F, and IL-22 in psoriatic lesions, contributing to disease pathogenesis.

    “In addition to Th17 cells, dermal γδ T cells respond to IL-23 and are a major source of IL-17A, IL-17F, and IL-22 cytokines in psoriatic lesions, making them additional contributors to disease pathogenesis [120, 121].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [120] Duerr, R. H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006). Genome-wide association study in inflammatory bowel disease identifying the IL23R gene highly associated with disease. source

      Not checked in the free run.

    • cites [121] Hueber, W. et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61, 1693–1700 (2012). An important clinical study showing that IL-17 blockade in Crohn’s disease is not only ineffective but exacerbates disease. source

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  • May combine two claims.

    Premisecitation

    Febrile temperature enhances Th17 cytokine production in vitro and promotes pathogenic gene expression and pro-inflammatory function in vivo.

    “Febrile temperature enhanced the production of cytokines by Th17 cells in vitro and promoted pathogenic gene expression and pro-inflammatory function in vivo.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [101] Papp, K. A. et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 371, 1675–1684 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The role of Th17 cells in mouse models of IBD is controversial, likely due to their dichotomous nature as mediators of tissue homeostasis that can become drivers of tissue inflammation.

    “The role of Th17 cells in mouse models of inflammatory bowel disease (IBD) is controversial, which is likely due to the dichotomous nature of intestinal Th17 cells, as they are mediators of tissue homeostasis yet can become drivers of tissue inflammation [37].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Yosef, N. et al. Dynamic regulatory network controlling TH17 cell differentiation. Nature 496, 461–468 (2013). source

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  • May combine two claims.

    Premisecitation

    IL-17-deficient mice are protected against collagen-induced arthritis and spontaneous arthritis in IL-1Rα−/− mice.

    “IL-17-deficient mice are protected against collagen-induced arthritis (CIA) [122] and from spontaneous arthritis in IL-1Rα−/− mice [123].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [122] Feagan, B. G. et al. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn’s disease: a randomised, double-blind, placebo-controlled phase 2 study. Lancet 389, 1699–1709 (2017). source

      Not checked in the free run.

    • cites [123] Sands, B. E. et al. Efficacy and safety of MEDI2070, an antibody against interleukin 23, in patients with moderate to severe Crohn’s disease: a phase 2a study. Gastroenterology 153, 77–86.e6 (2017). source

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  • May combine two claims.

    Premisecitation

    IL-17A-deficient mice show significantly attenuated EAE, while IL-17F-deficient mice show only marginally reduced EAE.

    “IL-17A-deficient mice exhibit significantly attenuated EAE disease, whereas IL-17F-deficient mice show marginally reduced EAE”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [111] Segal, B. M. et al. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol. 7, 796–804 (2008). source

      Not checked in the free run.

    • cites [112] Havrdova, E. et al. Activity of secukinumab, an anti-IL-17A antibody, on brain lesions in RRMS: results from a randomized, proof-of-concept study. J. Neurol. 263, 1287–1295 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the T cell transfer model of colitis, disease induction does not depend on IL-17A expression by T cells, but loss of both IL-17A and IL-17F abrogates T cell pathogenicity.

    “In the T cell transfer model of colitis, disease induction is not dependent on IL-17A-expression by T cells [125, 126], although loss of both IL-17A and IL-17F abrogated T cell pathogenicity [127].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [125] Harbour, S. N. et al. TH17 cells give rise to TH1 cells that are required for the pathogenesis of colitis. Proc. Natl Acad. Sci. USA 112, 7061–7066 (2015). source

      Not checked in the free run.

    • cites [126] Lee, Y. K. et al. Late developmental plasticity in the T helper 17 lineage. Immunity 30, 92–107 (2009). source

      Not checked in the free run.

    • cites [127] Annunziato, F. et al. Phenotypic and functional features of human TH17 cells. J. Exp. Med. 204, 1849–1861 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Th17 cells upregulate IL-10 and acquire a Tr1 phenotype during resolution of intestinal inflammation and re-establishment of homeostasis.

    “Th17 cells were additionally shown to upregulate expression of the anti-inflammatory cytokine IL-10 and acquire a T regulatory type 1 (Tr1) cell phenotype during the resolution of intestinal inflammation and re-establishment of homeostasis”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [104] Langley, R. G. et al. Secukinumab in plaque psoriasis—results of two phase 3 trials. N. Engl. J. Med. 371, 326–338 (2014). Two clinical trials demonstrating high efficacy of secukinumab in psoriasis with superior efficacy to previously approved psoriasis therapies. source

      Not checked in the free run.

    • cites [105] Griffiths, C. E. et al. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet 386, 541–551 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-23, IL-22, and IL-17A play essential roles in experimental psoriasis models and in psoriasis pathogenesis.

    “The Th17-associated cytokines IL-23, IL-22 and IL-17A have been shown to play essential roles in these models and in the pathogenesis of psoriasis [117–119].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [117] Genovese, M. C. et al. A phase II randomized study of subcutaneous ixekizumab, an anti-interleukin-17 monoclonal antibody, in rheumatoid arthritis patients who were naive to biologic agents or had an inadequate response to tumor necrosis factor inhibitors. Arthritis Rheumatol. 66, 1693–1704 (2014). source

      Not checked in the free run.

    • cites [118] Blanco, F. J. et al. Secukinumab in active rheumatoid arthritis: a phase III randomized, double-blind, active comparator- and placebo-controlled study. Arthritis Rheumatol. 69, 1144–1153 (2017). source

      Not checked in the free run.

    • cites [119] Fujino, S. et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut 52, 65–70 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blockade of IL-17A in Crohn's patients is ineffective and results in exacerbated colitis leading to study termination.

    “However, blockade of IL-17A in Crohn’s patients was found to be ineffective and instead resulted in exacerbated colitis leading to study termination [29, 49].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [29] Ghoreschi, K. et al. Generation of pathogenic TH17 cells in the absence of TGF-β signaling. Nature 467, 967–971 (2010). source

      Not checked in the free run.

    • cites [49] Ladinsky, M. S. et al. Endocytosis of commensal antigens by intestinal epithelial cells regulates mucosal T cell homeostasis. Science 363, eaat4042 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-17A inhibition is superior to placebo and improves symptoms in patients non-responsive to TNF targeting, suggesting a pathogenic role for IL-17A in RA.

    “IL-17A inhibition was superior to placebo and improved symptoms in patients non-responsive to TNF targeting, suggesting a pathogenic role for IL-17A in RA [150–152].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [150] Pawlak, M. et al. Induction of a colitogenic phenotype in TH1-like cells depends on interleukin-23 receptor signaling. Immunity 55, 1663–1679.e6 (2022). source

      Not checked in the free run.

    • cites [151]

      Not checked in the free run.

    • cites [152]

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Clinical results suggest that IL-23-specific inhibition may prevent development of pathogenic T cells while allowing IL-23-independent production of IL-17A, potentially from homeostatic Th17 cells, to maintain intestinal epithelial barrier integrity.

    “These clinical results suggest that IL-23-specific inhibition may prevent the development of pathogenic T cells, while allowing the IL-23 independent production of IL-17A, potentially from homeostatic Th17 cells, to maintain intestinal epithelial barrier integrity [130, 157].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [130] Paroni, M. et al. Recognition of viral and self-antigens by TH1 and TH1/TH17 central memory cells in patients with multiple sclerosis reveals distinct roles in immune surveillance and relapses. J. Allergy Clin. Immunol. 140, 797–808 (2017). source

      Not checked in the free run.

    • cites [157]

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Secukinumab is approved for ankylosing spondylitis, demonstrating a role of IL-17 in the pathology of multiple human autoimmune and inflammatory diseases.

    “Moreover, secukinumab has also been approved for treatment of ankylosing spondylitis [143], demonstrating a role of IL-17 in the pathology of multiple human autoimmune and inflammatory diseases.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [143] Miyauchi, E. et al. Gut microorganisms act together to exacerbate inflammation in spinal cords. Nature 585, 102–106 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-17 is highly expressed in active MS lesions, and Th17 cells mediate blood-brain barrier disruption via IL-17 and IL-22.

    “IL-17 was also found to be highly expressed in active MS lesions [144] and Th17 cells mediate blood-brain barrier disruption by the expression of IL-17 and IL-22 [145].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [144] Berer, K. et al. Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. Proc. Natl Acad. Sci. USA 114, 10719–10724 (2017). source

      Not checked in the free run.

    • cites [145] Lee, Y. K. et al. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 108, 4615–4622 (2011). This study describes that the induction of intestinal TH17 cells with SFB exacerbates EAE disease, providing evidence for a role of the intestinal TH17 population in extra-intestinal autoimmune disease. source

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  • May combine two claims.

    Premisecitation

    In psoriatic skin lesions, the majority of CD4+ and CD8+ T cells and γδ T cells express IL-17, and elevated IL-17A, IL-22, and IL-23 levels are found in active psoriasis.

    “In psoriatic skin lesions, the majority of CD4+ and CD8+ T cells, and γδ T cells, express IL-17 [134], and elevated IL-17A, IL-22 and IL-23 levels were found in patients with active psoriasis [135].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [134] McQualter, J. L. et al. Granulocyte macrophage colony-stimulating factor: a new putative therapeutic target in multiple sclerosis. J. Exp. Med. 194, 873–882 (2001). source

      Not checked in the free run.

    • cites [135] Lin, C. C. et al. Bhlhe40 controls cytokine production by T cells and is essential for pathogenicity in autoimmune neuroinflammation. Nat. Commun. 5, 3551 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In IBD, increased levels of IL-17 and IL-23 are found in colon biopsies, and multiple SNPs in IL23R are associated with susceptibility to IBD.

    “In IBD, increased levels of IL-17 and IL-23 were found in colon biopsies from patients and multiple single nucleotide polymorphisms in IL23R were associated with susceptibility to IBD [153, 154].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [153]

      Not checked in the free run.

    • cites [154]

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Th17 cells are major disease drivers in the T cell transfer model and the Il10−/− model of colitis.

    “Collectively, these data suggest that Th17 cells are major disease drivers in the transfer model and Il10−/− model of colitis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Secukinumab, an IL-17A inhibitor, was effective in reducing active lesions in patients with RRMS in a double-blind clinical trial (NCT01051817), but was not pursued further.

    “On the other hand, the IL-17A inhibitor secukinumab was found to be effective in reducing active lesions in patients with RRMS in a double-blind clinical trial (NCT01051817), but was not pursued further because of other competing orally available drugs [29, 30].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [29] Ghoreschi, K. et al. Generation of pathogenic TH17 cells in the absence of TGF-β signaling. Nature 467, 967–971 (2010). source

      Not checked in the free run.

    • cites [30] McGeachy, M. J. et al. TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell-mediated pathology. Nat. Immunol. 8, 1390–1397 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-17A and IL-17RA inhibitors (secukinumab, ixekizumab, brodalumab) are approved for moderate to severe plaque psoriasis and show superior efficacy to previously approved therapies, including TNF inhibitors and IL-23/IL-12 inhibitors, resulting in disease-free skin in up to 42% of patients.

    “IL-17A and IL-17RA inhibitors (secukinumab, ixekizumab, and brodalumab) are approved for the treatment of moderate to severe plaque psoriasis and show superior efficacy to previously approved therapies for psoriasis, including TNF inhibitors and IL-23/IL-12 inhibitors, resulting in disease-free skin in up to 42% of patients [28, 29, 139, 140].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [28] Schnell, A. et al. Stem-like intestinal TH17 cells give rise to pathogenic effector T cells during autoimmunity. Cell 184, 6281–6298 (2021). Analysis of combined single-cell RNA sequencing and T cell receptor sequencing of tissue TH17 cells during homeostasis and EAE, identifying a stem-like intestinal TH17 population that gives rise to pathogenic effector TH17 cells. source

      Not checked in the free run.

    • cites [29] Ghoreschi, K. et al. Generation of pathogenic TH17 cells in the absence of TGF-β signaling. Nature 467, 967–971 (2010). source

      Not checked in the free run.

    • cites [139] Wang, J. et al. Single-cell multiomics defines tolerogenic extrathymic Aire-expressing populations with unique homology to thymic epithelium. Sci. Immunol. 6, eabl5053 (2021). source

      Not checked in the free run.

    • cites [140] Kedmi, R. et al. A RORγt+ cell instructs gut microbiota-specific Treg cell differentiation. Nature 610, 737–743 (2022). source

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  • May combine two claims.

    Premisecitation

    Multiple studies found an association of IL-17 with rheumatoid arthritis, with elevated IL-17 and IL-17R in tissues and synovial fluids and synovial IL-17 levels correlating with disease progression.

    “Multiple studies found an association of IL-17 with rheumatoid arthritis (RA). Elevated levels of IL-17 and IL-17R were detected in tissues and synovial fluids from RA patients and synovial IL-17 levels were found to correlate with disease progression [147–149].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [147] Wu, H. J. et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32, 815–827 (2010). source

      Not checked in the free run.

    • cites [148] Krebs, C. F. et al. Autoimmune renal disease is exacerbated by S1P-receptor-1-dependent intestinal TH17 cell migration to the kidney. Immunity 45, 1078–1092 (2016). source

      Not checked in the free run.

    • cites [149] Hiltensperger, M. et al. Skin and gut imprinted helper T cell subsets exhibit distinct functional phenotypes in central nervous system autoimmunity. Nat. Immunol. 22, 880–892 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    CD8-like cells expressed both Cd4 and CD8+ T cell markers and were also recently reported in human IBD, and may represent a common phenomenon in T-cell-driven autoimmune tissue inflammation.

    “Interestingly, the CD8-like cells expressed both Cd4 and CD8+ T cell markers and were also recently reported in human IBD, and may thus represent a common phenomenon in T-cell-driven autoimmune tissue inflammation [166, 167].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [166]

      Not checked in the free run.

    • cites [167]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the intestine, Th17 cytokines IL-17A, IL-17F, and IL-22 mediate protective functions, but the requirement for IL-23 and RORγt in mouse models of colitis indicates potential involvement of Th17 cells in inducing intestinal inflammation.

    “In the intestine, Th17 cytokines IL-17A, IL-17F, and IL-22 were shown to mediate protective functions, but the requirement for IL-23 and RORγt in mouse models of colitis indicates the potential involvement of Th17 cells in inducing intestinal inflammation as well [127, 131, 132].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [127] Annunziato, F. et al. Phenotypic and functional features of human TH17 cells. J. Exp. Med. 204, 1849–1861 (2007). source

      Not checked in the free run.

    • cites [131] Jain, R. et al. Interleukin-23-induced transcription factor Blimp-1 promotes pathogenicity of T helper 17 cells. Immunity 44, 131–142 (2016). source

      Not checked in the free run.

    • cites [132] Sheng, W. et al. STAT5 programs a distinct subset of GM-CSF-producing T helper cells that is essential for autoimmune neuroinflammation. Cell Res. 24, 1387–1402 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In human autoimmune diseases, IL-17A- and IFNγ-expressing T cells are preferentially found at sites of inflammation and correlate with pathogenicity.

    “In human autoimmune diseases, IL-17A- and IFNγ-expressing T cells are preferentially found at sites of inflammation and correlate with pathogenicity [160–165].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [160]

      Not checked in the free run.

    • cites [161]

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    • cites [162]

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    • cites [163]

      Not checked in the free run.

    • cites [164]

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    • cites [165]

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  • May combine two claims.

    Premisecitation

    During EAE, ~80% of CNS-infiltrating CD4+ T cells originate from the Th17 lineage, and ~40% of these cells express IFNγ and ~40% express GM-CSF, indicating that a great proportion of GM-CSF+ T cells during EAE are derived from IL-17A-expressing cells.

    “In fact, during EAE, ~80% of CNS-infiltrating CD4+ T cells were found to originate from the Th17 lineage and ~40% of these cells expressed IFNγ and ~40% expressed GM-CSF, indicating that a great proportion of GM-CSF+ T cells during EAE are derived from IL-17A-expressing cells [76].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] Yang, X. O. et al. Regulation of inflammatory responses by IL-17F. J. Exp. Med. 205, 1063–1075 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    IL-23R signaling is more broadly relevant than previously thought and may provide an important target for inhibition of pathogenicity of multiple effector cells that mediate autoimmunity.

    “This suggests that IL-23R signaling is more broadly relevant than previously thought and that it may also provide an important target for inhibition of the pathogenicity of multiple effector cells that mediate autoimmunity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    GM-CSF-deficient mice are resistant to EAE, and GM-CSF+ T cells are enriched in patients with MS.

    “Similar to IL-17-deficient mice, GM-CSF-deficient mice are resistant to EAE [176] and GM-CSF+ T cells are enriched in patients with MS [36].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [176]

      Not checked in the free run.

    • cites [36] Ciofani, M. et al. A validated regulatory network for TH17 cell specification. Cell 151, 289–303 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intestinal Th17 cells are important mediators of intestinal epithelial barrier integrity, but have also been implicated in driving intestinal inflammation and in regulating autoimmune diseases outside the intestine.

    “Intestinal Th17 cells are important mediators of intestinal epithelial barrier integrity [130, 157], however, they have also been implicated in driving intestinal inflammation and, interestingly, in regulating autoimmune diseases outside of the intestine (Figure 4).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [130] Paroni, M. et al. Recognition of viral and self-antigens by TH1 and TH1/TH17 central memory cells in patients with multiple sclerosis reveals distinct roles in immune surveillance and relapses. J. Allergy Clin. Immunol. 140, 797–808 (2017). source

      Not checked in the free run.

    • cites [157]

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    No master transcription factor for GM-CSF+ T cells has been identified, and no distinct mechanisms or differentiation conditions specifically induce GM-CSF in naïve CD4+ T cells.

    “To date, no master transcription factor for GM-CSF+ T cells has been identified and no distinct mechanisms or differentiation conditions have been identified that specifically induce GM-CSF in naïve CD4+ T cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Specific ablation of GM-CSF expression in T cells during EAE leads to unchanged invasion of T cells into the CNS, but the infiltrating cells induce significantly milder disease with reduced numbers of CNS-invading monocyte-derived cells.

    “Specific ablation of GM-CSF expression in T cells during EAE leads to unchanged invasion of T cells into the CNS, but the infiltrating cells induce a significantly milder disease with reduced numbers of CNS-invading monocyte-derived cells [33].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Xu, M. et al. c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. Nature 554, 373–377 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Fate-mapping studies revealed an in vivo relationship between IL-17-expressing Th17 cells and GM-CSF+ T cells, indicating that GM-CSF+ cells are either current Th17 cells or ex-Th17 cells.

    “However, fate-mapping studies revealed an in vivo relationship of IL-17-expressing Th17 cells and GM-CSF+ T cells, indicating that GM-CSF+ cells are either current Th17 cells or ex-Th17 cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The intestinal microbiota is required for the development of EAE, as germ-free mice are protected against EAE.

    “The intestinal microbiota is required for the development of EAE, as germ-free mice are protected against EAE [50, 184].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [50] Sano, T. et al. An IL-23R/IL-22 circuit regulates epithelial serum amyloid A to promote local effector TH17 responses. Cell 163, 381–393 (2015). source

      Not checked in the free run.

    • cites [184]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    APCs required for induction of homeostatic Th17 cells by SFB are dependent on CCR7 and express CD11c, and are distinct from APCs inducing H. hepaticus-specific pathogenic Th17 cells.

    “While the precise identity of these APCs is not yet known, they are distinct from APCs required for the induction of homeostatic Th17 cells by SFB, as those cells are dependent on CCR7 and express CD11c [182] (unpublished).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [182]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two intestinal microorganisms, Erysipelotrichaceae and Lactobacillus reuteri, act together to promote EAE; Erysipelotrichaceae induces Th17 cells in the small intestine and is synergistic with L. reuteri, which has peptides mimicking MOG, and co-colonized mice develop more severe EAE than germ-free or mono-colonized mice.

    “In a recent study two intestinal microorganisms were found to act together to promote EAE disease [185]. Erysipelotrichaceae acted as an adjuvant that induced Th17 cells in the small intestine and was synergistic in promoting EAE with Lactobacillus reuteri, which possesses peptides that show molecular mimicry with MOG. Mice co-colonized with both strains developed more severe EAE disease than germ”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [185]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Anti-tumor immunity and responses to checkpoint blockade therapy are influenced and regulated by the gut microbiota.

    “Interestingly, anti-tumor immunity [190] and responses to check-point blockade therapy [191–195] have recently been shown to be influenced and regulated by the gut microbiota.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [190]

      Not checked in the free run.

    • cites [191]

      Not checked in the free run.

    • cites [192]

      Not checked in the free run.

    • cites [193]

      Not checked in the free run.

    • cites [194]

      Not checked in the free run.

    • cites [195]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hiltensperger et al. identified inguinal lymph node-derived T cells (i-T cells) in EAE with a distinct transcriptomic signature from mesenteric lymph node-derived T cells (m-T cells); i-T cells are marked by CXCR6 and infiltrate white matter, while m-T cells are marked by P2RX7 and migrate to gray matter, indicating that the priming site regulates T cell function.

    “One study by Hiltensperger et al. [188] performed site-specific in vivo labeling of T cells in EAE and identified inguinal lymph node-derived T cells (i-T cells) as exhibiting a distinct transcriptomic signature from mesenteric lymph node-derived T cells (m-T cells). While i-T cells are marked by CXCR6 and infiltrate white matter, m-Tcells are marked by P2RX7 and migrate to the gray matter, indic”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [188]

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Single-cell technologies have revealed significant heterogeneity within the Th17 population in vivo, shedding light on mechanisms underlying diversity between pathogenic and homeostatic Th17 states.

    “In the last few years, the use of single-cell technologies has revealed a significant amount of heterogeneity within the Th17 population in vivo, shedding light on mechanisms that underlie the diversity between pathogenic Th17 and homeostatic Th17 states.”
    Quote in the paperSubstantial claim
83 of 83

  • The paper relies on this without support.

    IL-23 produced by macrophages and dendritic cells drives differentiation and expansion of IL-22+ and IL-17A+ Th17 cells that activate tissue cells including keratinocytes and fibroblasts, mediating tissue inflammation.

    “IL-23, produced by macrophages and dendritic cells, drives the differentiation and expansion of IL-22+ and IL-17A+ Th17 cells that activate the surrounding tissue cells including keratinocytes and fibroblasts, thereby mediating tissue inflammation.”

  • The paper relies on this without support.

    Expansion of pro-inflammatory Th17 cells is restrained by H. hepaticus-specific RORγt+FOXP3+ iTreg that depend on c-MAF.

    “Expansion of these pro-inflammatory Th17 cells is restrained by H. hepaticus-specific RORγt+FOXP3+ regulatory T cells (iTreg) that are dependent on the expression of the transcription factor c-MAF.”

  • The paper relies on this without support.

    The homeostatic SLAMF6+ cell population shows multiple parallels in transcriptional phenotype and function to previously described stem-like CD8+ T cells in tumors and in response to LCMV infection.

    “On an additional note, the homeostatic SLAMF6+ cell population shows multiple parallels in transcriptional phenotype and function to previously described stem-like CD8+ T cells in tumors and in response to LCMV infection.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • IL-23 is described both as a Th17 differentiation factor and as not being one

    Minor

    The introduction says IL-23 acts on already differentiated Th17 cells rather than inducing their differentiation. A later section instead calls IL-23 an essential mediator of Th17 differentiation.

1 of 1

The citation lists haven’t been fetched yet

References 203 · Cited by 286

Authors
Schnell, A., Littman, D. R., & Kuchroo, V. K.
Affiliations
  • Broad Institute (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
  • Littman, Dan R.
  • Kuchroo, Vijay K.
ORCID
Venue
Nature Immunology
Publisher
Springer Science and Business Media LLC
Published
2023-01
Volume
24
Issue
1
Pages
19-29
ISSN
  • 1529-2908 (ISSN-L)
  • 1529-2916
DOI
10.1038/s41590-022-01387-9
PMC
PMC10795475
OpenAlex
W4313528847
Semantic Scholar
19e209001f9b1a072f6f7756be1b2812d33c111d
Cited by
286
References
203
Citations by year
2026: 82 · 2025: 101 · 2024: 75 · 2023: 28
FWCI
7.91
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
U.S. Department of Health & Human Services | NIH | National Center for Research Resources (R01NS045937, R01NS30843, R01AI144166, P01AI073748, P01AI039671, P01AI056299, R01AI158687, RO1CA255635)
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 cells, T cell heterogeneity, T cell plasticity, tissue inflammation, intestinal mucosa, tissue homeostasis, autoimmune disease, inflammatory diseases, single-cell technologies, fate mapping, T cell subsets
MeSH terms
Cell Plasticity, Animals, Disease Models, Animal, Inflammation, T-Lymphocyte Subsets, Mice, Th17 Cells

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