ArticleJournal of immunology (Baltimore, Md. : 1950)2023
Disabled C3ar1/C5ar1 Signaling in Foxp3+ T Regulatory Cells Leads to TSDR Demethylation and Long-Term Stability.
Article in Journal of immunology (Baltimore, Md. : 1950), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 3 citations in OpenAlex.
- Next-Generation regulatory T cell therapies: Translational considerations for inflammatory bowel disease.Human immunology · 2026Review
- Unveiling natural anti-inflammatory compounds for sinusitis treatments by modulating FOXP3, C5aR1, and LIF.Frontiers in immunology · 2026Review
- Regulatory T cell therapy in autoimmune and immune-mediated diseases: from basic research to clinical practice and future perspectives.Frontiers in immunology · 2026Review
- Regulatory T cells in homeostasis and disease: molecular mechanisms and therapeutic potential.Signal transduction and targeted therapy · 2025Review
- Targeting T regulatory (TCancer drug resistance (Alhambra, Calif.) · 2024Review
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Demethylation of the T regulatory cell (Treg)-specific demethylation region (TSDR) of the Foxp3 gene is the hallmark of Foxp3+ Treg stability, but the cellular signaling that programs this epigenetic state remains undefined. In this article, we show that suppressed C3a and C5a receptor (C3ar1/C5ar1) signaling in murine Tregs plays an obligate role. Murine C3ar1-/-C5ar1-/- Foxp3+ cells showed increased suppressor of cytokine signaling 1/2/3 expression, vitamin C stabilization, and ten-eleven translocation (TET) 1, TET2, and TET3 expression, all of which are linked to Treg stability. C3ar1-/-C5ar1-/- Foxp3+ cells additionally were devoid of BRD4 signaling that primes Th17 cell lineage commitment. Orally induced OVA-specific C3ar1-/-C5ar1-/- Foxp3+ OT-II Tregs transferred to OVA-immunized wild-type recipients remained >90% Foxp3+ out to 4 mo, whereas identically generated CD55-/- (DAF-/-) Foxp3+ OT-II Tregs (in which C3ar1/C5ar1 signaling is potentiated) lost >75% of Foxp3 expression by 14 d. After 4 mo in vivo, the C3ar1-/-C5ar1-/- Foxp3+ OT-II Tregs fully retained Foxp3 expression even with OVA challenge and produced copious TGF-β and IL-10. Their TSDR was demethylated comparably with that of thymic Tregs. They exhibited nuclear translocation of NFAT and NF-κB reported to stabilize thymic Tregs by inducing hairpin looping of the TSDR to the Foxp3 promoter. Thus, disabled CD4+ cell C3ar1/C5ar1 signaling triggers the sequential cellular events that lead to demethylation of the Foxp3 TSDR.
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