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TGFβ in the Context of an Inflammatory Cytokine Milieu Supports De Novo Differentiation of IL-17-Producing T Cells
Open accessAbstract
We describe de novo generation of IL-17-producing T cells from naive CD4 T cells, induced in cocultures of naive CD4 T cells and naturally occurring CD4+ CD25+ T cells (Treg) in the presence of TLR3, TLR4, or TLR9 stimuli. Treg can be substituted by TGFbeta1, which, together with the proinflammatory cytokine IL-6, supports the differentiation of IL-17-producing T cells, a process that is amplified by IL-1beta and TNFalpha. We could not detect a role for IL-23 in the differentiation of IL-17-producing T cells but confirmed its importance for their survival and expansion. Transcription factors GATA-3 and T-bet, as well as its target Hlx, are absent in IL-17-producing T cells, and they do not express the negative regulator for TGFbeta signaling, Smad7. Our data indicate that, in the presence of IL-6, TGFbeta1 subverts Th1 and Th2 differentiation for the generation of IL-17-producing T cells.
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“Here, we report that in addition to its key role in Th17 cell induction (3, 4), there is an absolute requirement for persistent IL-6 signaling to maintain the Th17 genetic program, and thus Th17 cells.”
From T H 17 cells require ongoing classic IL-6 receptor signaling to retain transcriptional and functional identity (2020) · cites this paper as [3]
In the citing paper
“IL-6 together with TGFβ induces Th17 cells (Fig. 2) (164).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [164]
In the citing paper
“The produced IL-6 further induces Th17 cell differentiation through STAT3 in the presence of TGFβ, IL-1β and IL-23, all of which are rich in inflammatory lesions and tumor microenvironments (164, 166, 169–171, 174, 175).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [164]
In the citing paper
“Th17 cells were established as an independent T helper cell subset with the discovery of signature cytokines IL-17A, IL-17F, and IL-22, lineage-specific differentiation factors, and dedicated or “master” transcription factors”
From TH17 cell heterogeneity and its role in tissue inflammation (2023) · cites this paper as [10]
In the citing paper
“In response to TGF-β in vitro as well as in vivo, many T cells co-express RORγt and Foxp3 (Veldhoen et al., 2006; Yang et al., 2008a).”
From Control of TH17/Treg Balance by Hypoxia-Inducible Factor 1 (2011) · cites this paper as Veldhoen et al., 2006
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Swamy, M., Jamora, C., Havran, W. L., & Hayday, A. (2010) · Nature Immunology · doi:10.1038/ni.1905 · Cited by 277
NLRP3 inflammasome driven liver injury and fibrosis: roles of IL-17 and TNF in mice
Wree, A., McGeough, M. D., Inzaugarat, M. E., Eguchi, A., Schuster, S., Johnson, C. D., Peña, C. A., Geisler, L. J., Papouchado, B. G., Hoffman, H. M., et al. (2018) · Hepatology · doi:10.1002/hep.29523 · Cited by 266
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Tuning Microenvironments: Induction of Regulatory T Cells by Dendritic Cells
Belkaid, Y., & Oldenhove, G. (2008) · Immunity · doi:10.1016/j.immuni.2008.08.005 · Cited by 278
IκBζ regulates TH17 development by cooperating with ROR nuclear receptors
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CCR6 and NK1.1 distinguish between IL‐17A and IFN‐γ‐producing γδ effector T cells
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Increased Circulating Pro-Inflammatory Cytokines and Th17 Lymphocytes in Hashimoto’s Thyroiditis
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Development and function of TH17 cells in health and disease
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CD4 T-cell differentiation and inflammatory bowel disease
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IL-17 and IL-22 are associated with protection against human kala azar caused by Leishmania donovani
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TGF-β: the sword, the wand, and the shield of FOXP3+ regulatory T cells
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“However, it is quite surprising to learn that Tregs can empower instead of suppress naı̈ve T cells to differentiate into effector Th17 (Lohr et al., 2006; Veldhoen et al., 2006; LeibundGut-Landmann et al., 2007; Xu et al., 2007; Vokaer et al., 2010; Pandiyan et al., 2011).”
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T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17
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“IL-6, in cooperation with TGF-β, is reported to be critical for the differentiation of Th17 cells from naive CD4 T cells (15, 24, 25).”
BackgroundRole of IL-17 and Th17 Cells in Liver Diseases
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“Th17 cells are a more recently discovered subset of CD4+ T-helper cells characterized by the production of their signature cytokine IL-17.”
BackgroundInterleukin-17 in chronic inflammatory neurological diseases
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Interleukin‐17 as an Effector Molecule of Innate and Acquired Immunity against Infections
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“The development of Th17 cells from naive CD4+ T cells is directed by IL-6 in combination with transforming growth factor-b (TGF-b) (Bettelli et al., 2006; Mangan et al., 2006), and this process is enhanced by the presence of IL-1b (Veldhoen et al., 2006).”
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Metadata
- Authors
- Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M., & Stockinger, B.
- Affiliations
- National Institute for Medical Research (GB)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Stockinger, Brigitta
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2006-02
- Volume
- 24
- Issue
- 2
- Pages
- 179-189
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2112866067
- Cited by
- 3,605
- References
- 70
- Citations by year
- 2026: 41 · 2025: 54 · 2024: 71 · 2023: 91 · 2022: 110 · 2021: 149 · 2020: 113 · 2019: 114 · 2018: 122 · 2017: 158 · 2016: 138 · 2015: 172 · 2014: 182 · 2013: 219 · 2012: 246
- FWCI
- 126.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (AI30663, R01AI030663)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- IL-17-producing T cells, TGF-β1, Th17 cell differentiation, regulatory T cells, interleukin-6, TLR3, TLR4, TLR9, IL-1β, TNF-α, IL-23, GATA3, T-bet, Smad7, Th1/Th2 differentiation, naive CD4+ T cells, inflammatory cytokines
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, Dendritic Cells, Membrane Glycoproteins, Mice, Inbred C57BL, Mice, Transgenic, T-Lymphocytes, CD4-Positive T-Lymphocytes, Lymphocyte Subsets, Cytokines, Transforming Growth Factor beta, Receptors, Interleukin-1, Mice, Knockout, Th1 Cells, Th2 Cells, Interleukin-17, T-Lymphocytes, Regulatory, Mice, Smad7 Protein, Transforming Growth Factor beta1
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