Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis

Komatsu, Noriko; Okamoto, Kazuo; Sawa, Shinichiro; Nakashima, Tomoki; Oh-hora, Masatsugu; Kodama, Tatsuhiko; Tanaka, Sakae; Bluestone, Jeffrey A; Takayanagi, Hiroshi

doi:10.1038/nm.3432

Cited by 1,153T-cell and B-cell ImmunologyPsoriasis: Treatment and PathogenesisRheumatoid Arthritis Research and Therapies

Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis

Komatsu, Noriko, Okamoto, Kazuo, Sawa, Shinichiro, Nakashima, Tomoki, Oh-hora, Masatsugu, Kodama, Tatsuhiko, Tanaka, Sakae, Bluestone, Jeffrey A +1 more·2014·Nature Medicine

DOI 10.1038/nm.3432

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Abstract

Autoimmune diseases often result from an imbalance between regulatory T (Treg) cells and interleukin-17 (IL-17)-producing T helper (TH17) cells; the origin of the latter cells remains largely unknown. Foxp3 is indispensable for the suppressive function of Treg cells, but the stability of Foxp3 has been under debate. Here we show that TH17 cells originating from Foxp3(+) T cells have a key role in the pathogenesis of autoimmune arthritis. Under arthritic conditions, CD25(lo)Foxp3(+)CD4(+) T cells lose Foxp3 expression (herein called exFoxp3 cells) and undergo transdifferentiation into TH17 cells. Fate mapping analysis showed that IL-17-expressing exFoxp3 T (exFoxp3 TH17) cells accumulated in inflamed joints. The conversion of Foxp3(+)CD4(+) T cells to TH17 cells was mediated by synovial fibroblast-derived IL-6. These exFoxp3 TH17 cells were more potent osteoclastogenic T cells than were naive CD4(+) T cell-derived TH17 cells. Notably, exFoxp3 TH17 cells were characterized by the expression of Sox4, chemokine (C-C motif) receptor 6 (CCR6), chemokine (C-C motif) ligand 20 (CCL20), IL-23 receptor (IL-23R) and receptor activator of NF-κB ligand (RANKL, also called TNFSF11). Adoptive transfer of autoreactive, antigen-experienced CD25(lo)Foxp3(+)CD4(+) T cells into mice followed by secondary immunization with collagen accelerated the onset and increased the severity of arthritis and was associated with the loss of Foxp3 expression in the majority of transferred T cells. We observed IL-17(+)Foxp3(+) T cells in the synovium of subjects with active rheumatoid arthritis (RA), which suggests that plastic Foxp3(+) T cells contribute to the pathogenesis of RA. These findings establish the pathological importance of Foxp3 instability in the generation of pathogenic TH17 cells in autoimmunity.

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A reduction in Treg numbers under sustained disease leads to increased Th17/Treg imbalance and aberrant activation of pro-inflammatory T cell subsets, resulting in hepatocyte injury and exacerbation of liver inflammation.
“Since Tregs are immunoregulatory cells capable of suppressing pro-inflammatory cytokine production by effector T cells, such as Th1 and Th17 cells (Workman et al. 2009), a reduction in Treg numbers under sustained disease conditions leads to an increased Th17/Treg imbalance and aberrant activation of pro-inflammatory T cell subsets, ultimately resulting in hepatocyte injury and exacerbation of”
From The double-edged sword of regulatory T cells in MASLD: from inflammation control to fibrosis promotion (2026) · cites this paper as Komatsu et al. 2014
The inflammatory milieu in chronic inflammation destabilizes Foxp3 expression in Tregs and impairs their suppressive functions.
“This inflammatory milieu destabilizes Foxp3 expression in Tregs and impairs their suppressive functions (Campbell and Koch 2011; Komatsu et al. 2014).”
From The double-edged sword of regulatory T cells in MASLD: from inflammation control to fibrosis promotion (2026) · cites this paper as Komatsu et al. 2014

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Authors: Komatsu, N., Okamoto, K., Sawa, S., Nakashima, T., Oh-hora, M., Kodama, T., Tanaka, S., Bluestone, J. A., & Takayanagi, H.
Affiliations: Japan Science and Technology Agency (JP)
Tokyo Medical and Dental University (JP)
Research Center for Advanced Science and Technology, The University of Tokyo (JP)
The University of Tokyo (JP)
University of California, San Francisco (US)
The University of Western Australia (AU)
Corresponding author: Takayanagi, Hiroshi
ORCID: Okamoto, Kazuo
Sawa, Shinichiro
Nakashima, Tomoki
Kodama, Tatsuhiko
Tanaka, Sakae
Bluestone, Jeffrey A
Takayanagi, Hiroshi
Venue: Nature Medicine
Publisher: Springer Science and Business Media LLC
Published: 2013-12-22
Volume: 20
Issue: 1
Pages: 62-68
ISSN: 1078-8956 (ISSN-L)
1546-170X
DOI: 10.1038/nm.3432
OpenAlex: W2090069133
Cited by: 1,153
References: 42
Citations by year: 2026: 66 · 2025: 90 · 2024: 103 · 2023: 87 · 2022: 107 · 2021: 113 · 2020: 101 · 2019: 80 · 2018: 93 · 2017: 74 · 2016: 94 · 2015: 90 · 2014: 54 · 2012: 1
FWCI: 43.91
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Medicine (publishedVersion)
PubMed (publishedVersion)
UWA Profiles and Research Repository (UWA) (submittedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: Japan Society for the Promotion of Science (25670188, 23689075, 25670773, 23590565, 24111001, 24390412, 25670228)
National Institute of Allergy and Infectious Diseases (R01AI046643)
Topics: Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
Keywords: Foxp3+ regulatory T cells, Th17 cells, autoimmune arthritis, rheumatoid arthritis, synovial fibroblasts, interleukin-6, osteoclastogenesis, IL-17, IL23R, RANKL, CCR6, CCL20, SOX4
MeSH terms: Animals, Arthritis, Autoimmune Diseases, Cell Differentiation, Flow Cytometry, Humans, Mice, Inbred C57BL, Synovial Membrane, CD4-Positive T-Lymphocytes, Adoptive Transfer, Oligonucleotide Array Sequence Analysis, Mice, Forkhead Transcription Factors, Gene Knock-In Techniques, Th17 Cells

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Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis

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