Aug 2026· Science Advances· Vol 12· 0 citations· 75 references
Medicine
TL;DR
It is shown that the histone variant H3.3 is enriched in tissue Tregs compared to splenic Tregs and its chaperone Hira is a critical regulator of Treg effector program, revealing a previously unreported epigenetic mechanism critical for Treg effector differentiation and function.
Abstract
Foxp3+ regulatory T (Treg) cells need to differentiate into effector Treg (eTreg) cells to maintain immune tolerance and tissue homeostasis. While several transcription factors such as Batf and JunB have been reported to be essential for eTreg differentiation and function, the underlying epigenetic mechanism remains unclear. Here, we show that the histone variant H3.3 is enriched in tissue Tregs compared to splenic Tregs and its chaperone Hira is a critical regulator of Treg effector program. Treg specific-deletion of Hira resulted in reduced eTreg population, impaired suppressive function and multi-organ inflammation in mice. Mechanistically, Hira-dependent H3.3 deposition establishes a permissive epigenetic environment by enhancing chromatin accessibility, facilitating H3K36me3 and preventing H3K27me3 modifications on loci of genes enriched for AP-1 family binding motifs and associated with Treg effector function. Furthermore, overexpression of Batf in Hira-deficient Treg cells largely ameliorates their regulatory defects. Together, our findings reveal a previously unreported epigenetic mechanism critical for Treg effector differentiation and function.
It is shown that TIF1γ-deficient Treg cells lose Foxp3 expression and acquire effector phenotypes in a cell-intrinsic manner upon inflammatory challenge, and TIF1γ is identified as a critical regulator of Treg cell stability that restrains β-catenin–TCF7 signaling.
Eugenio Contreras-Castillo, Jesús Daniel Zambrano-Romero, H. N. Núñez-Martínez et al.· Nature Immunology· 1 citation
CHD4 is identified as a critical epigenetic regulator of Treg lineage stability and pharmacological targeting of the CHD4/NuRD axis is established as a promising strategy to selectively disrupt tumor-associated Tregs and enhance antitumor immunity.
Yan Xiong, Li-Qing Wang, Martina Minisini et al.· bioRxiv· 0 citations
The study depicts an epigenetic polarity governing Treg-mediated immune tolerance, highlighting a fundamental asymmetry at the epigenetic level that differentially regulates Treg and conventional T cells.
Wenjun Huang, Yongqiang Feng, Jun Li et al.· Journal of Immunology· 0 citations
CD4+ regulatory T cells (Tregs) are essential for maintaining immune homeostasis and preventing autoimmunity. Tregs primarily develop in the thymus, but can also arise from naïve CD4+ T cells in the periphery (pTregs) or be generated in vitro (iTregs). However, a major limitation of Treg-based therapies is the instability and plasticity of pTregs and iTregs. In contrast, tTregs have been shown to exhibit stable suppressive capacity, largely due to thymic-derived signals that epigenetically reinforce the Treg program. Elucidating the mechanisms governing Treg differentiation, stability, and function is therefore critical for improving Treg-based therapies.
We generated single-cell multiome data from human fetal and pediatric thymuses. We developed various analytical frameworks for unravelling gene regulatory networks (GRNs) involved in Treg lineage commitment. We identified candidate transcription factors (TFs) involved in thymic Treg differentiation and validated these TFs using a CRISPR-Cas9 KO system in primary human thymocytes.
GRN analysis revealed key driver TFs, such as FOXP3, REL and IKZF2 within CD4+ Tregs. Comparison of GRNs between mature CD4+ Tregs and conventional CD4+ T cells further reveals TFs related to TCR signaling and other novel TFs. Finally, candidate TFs including IRF4, REL, FOXO1, BATF and others were validated utilizing a CRISPR-Cas9 KO system.
We generated a single cell multiome atlas of fetal and pediatric thymuses and unravel GRNs involved in Treg lineage-specific differentiation. We develop novel analytical frameworks to identify lineage-specific driver TFs in Tregs and validated these by KO of primary human thymocytes. This framework provides an important mapping of GRNs involved in thymic T cell differentiation, particularly focusing on Tregs and will serve as an important basis for understanding Treg biology and improving Treg-based therapies.
Creative-Pioneering Researchers Program (800-20230490) Seoul National University
Hematopoiesis and Immune System Development (HEM)
B. Lee, Ioannis Sarropoulos, Yoonseo Park et al.· Journal of Immunology· 0 citations
Findings highlight a HuR-SerpinB9 axis that regulates T-cell senescence and persistence, offering a potential therapeutic target in cancer and autoimmune diseases.
P. Chakraborty, Mrinmoyee Majumder, W. Wofford et al.· Journal of Immunology· 0 citations
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