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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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“transforming growth factor b1 (TGF-b1) [42,7,8].”
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From interleukin-23 to T-helper 17 cells: human T-helper cell differentiation revisited
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Nickoloff, B. J., Qin, J., & Nestle, F. O. (2007) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-007-0039-2 · Cited by 218
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A novel role of IL-17–producing lymphocytes in mediating lytic bone disease in multiple myeloma
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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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