Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells
Abstract
On activation, T cells undergo distinct developmental pathways, attaining specialized properties and effector functions. T-helper (T(H)) cells are traditionally thought to differentiate into T(H)1 and T(H)2 cell subsets. T(H)1 cells are necessary to clear intracellular pathogens and T(H)2 cells are important for clearing extracellular organisms. Recently, a subset of interleukin (IL)-17-producing T (T(H)17) cells distinct from T(H)1 or T(H)2 cells has been described and shown to have a crucial role in the induction of autoimmune tissue injury. In contrast, CD4+CD25+Foxp3+ regulatory T (T(reg)) cells inhibit autoimmunity and protect against tissue injury. Transforming growth factor-beta (TGF-beta) is a critical differentiation factor for the generation of T(reg) cells. Here we show, using mice with a reporter introduced into the endogenous Foxp3 locus, that IL-6, an acute phase protein induced during inflammation, completely inhibits the generation of Foxp3+ T(reg) cells induced by TGF-beta. We also demonstrate that IL-23 is not the differentiation factor for the generation of T(H)17 cells. Instead, IL-6 and TGF-beta together induce the differentiation of pathogenic T(H)17 cells from naive T cells. Our data demonstrate a dichotomy in the generation of pathogenic (T(H)17) T cells that induce autoimmunity and regulatory (Foxp3+) T cells that inhibit autoimmune tissue injury.
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Th17 differentiation is on the order of 5 days.
“Immediate early gene transcription is on the order of minutes [25], while Th17 differentiation is on the order of 5 days [26].”
From A Model for How Signal Duration Can Determine Distinct Outcomes of Gene Transcription Programs (2012) · cites this paper as [26]
There is an absolute requirement for persistent IL-6 signaling to maintain the Th17 genetic program, and thus Th17 cells.
“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 <sub>H</sub> 17 cells require ongoing classic IL-6 receptor signaling to retain transcriptional and functional identity (2020) · cites this paper as [4]
IL-6 inhibits the TGFβ-induced generation of Treg cells.
“On the other hand, IL-6 inhibits the TGFβ-induced generation of Treg cells (166).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [166]
Produced IL-6 further induces Th17 cell differentiation through STAT3 in the presence of TGFβ, IL-1β and IL-23, which are rich in inflammatory lesions and tumor microenvironments.
“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 [166]
Th17 cells are an independent T helper cell subset.
“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 [11]
TH17 and Treg cells share a common requirement for TGF-β in their differentiation despite expressing distinct transcriptional regulators (RORγt vs. Foxp3) and demonstrating opposing functions.
“TH17 and Treg cells share a common requirement for TGF-p in their differentiation requirements despite expressing distinct transcriptional regulators (RORγt vs. Foxp3 respectively) and demonstrating opposing functions (inflammatory vs. anti-inflammatory)(Bettelli et al., 2006; Dong, 2008; Littman and Rudensky, 2010; Mangan et al., 2006; O'Quinn et al., 2008; Veldhoen et al., 2006).”
From Control of TH17/Treg Balance by Hypoxia-Inducible Factor 1 (2011) · cites this paper as Bettelli et al., 2006
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- Authors
- Bettelli, E., Carrier, Y., Gao, W., Korn, T., Strom, T. B., Oukka, M., Weiner, H. L., & Kuchroo, V. K.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Corresponding author
- Oukka, Mohamed
- Kuchroo, Vijay K.
- Venue
- Nature
- Published
- 2006-04-30
- Volume
- 441
- Issue
- 7090
- Pages
- 235-238
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2155779547
- Cited by
- 6,992
- References
- 24
- Citations by year
- 2026: 158 · 2025: 162 · 2024: 195 · 2023: 221 · 2022: 284 · 2021: 309 · 2020: 345 · 2019: 288 · 2018: 293 · 2017: 297 · 2016: 316 · 2015: 410 · 2014: 401 · 2013: 432 · 2012: 481
- FWCI
- 175.45
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Multiple Sclerosis Society
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- 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 › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Keywords
- Th17 cells, regulatory T cells, Foxp3, TGF-beta, interleukin-6, IL-23, T cell differentiation, autoimmunity, naive T cells
- MeSH terms
- Animals, Cell Differentiation, Central Nervous System, Receptors, Interleukin-2, Autoimmunity, CD4 Antigens, Interleukin-6, Cytokines, Transforming Growth Factor beta, Th1 Cells, Th2 Cells, Interleukin-17, Mice, Forkhead Transcription Factors
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