Wdr82-COMPASS coordinates Foxp3 and TCR signaling to sustain T reg cell control of microbiota-driven intestinal inflammation
Regulatory T cells (T reg cells) maintain immune tolerance, but how broadly acting epigenetic pathways are selectively used by T reg cells versus conventional T cells (T conv cells) remains unclear. Here, we identify the COMPASS–trimethylation of histone H3 lysine 4 (H3K4me3) pathway, through its Wdr82 component, as a key epigenetic regulator that preferentially supports T reg cell development and function. Although Wdr82 deficiency broadly impairs T cell activation, T cell–specific deletion paradoxically causes progressive, microbiota-dependent intestinal inflammation and expansion of inflammatory T conv cell programs. This pathology is prevented by microbiome depletion or transfer of wild-type T reg cells, indicating a primary defect in T reg cell–mediated tolerance. Mechanistically, Wdr82/COMPASS promotes Foxp3 induction, maintains H3K4me3 and chromatin accessibility at T reg cell–associated genes, and restrains effector programs within the T reg cell lineage. Foxp3 coordinates with COMPASS components in a T cell receptor/costimulation-dependent manner, linking antigen receptor signaling to chromatin regulation. Together, these findings reveal selective integration of a broadly active epigenetic pathway into the Foxp3-centered regulatory hierarchy that sustains T reg cell control of microbiota-driven intestinal inflammation.
Authors
- Ming-Hong He (ORCID: https://orcid.org/0000-0001-9978-7218)
- Anthony A. High (ORCID: https://orcid.org/0000-0003-2323-5649)
- Xiaolei Hao (ORCID: https://orcid.org/0000-0003-3413-2338)
- Shondra M. Pruett‐Miller (ORCID: https://orcid.org/0000-0002-3793-585X)
- 黄文军 (ORCID: https://orcid.org/0009-0005-0002-3426)
- Min-Jhen Jheng
- Menglin Jiang (ORCID: https://orcid.org/0000-0002-1660-9916)
- Yongqiang Feng (ORCID: https://orcid.org/0000-0002-2320-5063)
- Lu Bai (ORCID: https://orcid.org/0000-0002-8779-336X)
- Hongjian Jin (ORCID: https://orcid.org/0000-0003-3833-7170)
- Beisi Xu (ORCID: https://orcid.org/0000-0003-0099-858X)
- Ti‐Cheng Chang (ORCID: https://orcid.org/0000-0001-5302-9147)
- Zuo‐Fei Yuan (ORCID: https://orcid.org/0000-0003-1252-6766)
- Wenjie Qi (ORCID: https://orcid.org/0009-0006-0656-567X)
- Laura J. Janke (ORCID: https://orcid.org/0000-0002-9871-6239)
- Kiran Kodali (ORCID: https://orcid.org/0000-0002-0854-1405)
- Wojciech Rosikiewicz (ORCID: https://orcid.org/0000-0001-7031-3430)
- Jun Li (ORCID: https://orcid.org/0000-0002-2611-8918)
- Lei Li (ORCID: https://orcid.org/0000-0002-8828-5199)
- Siwei Zhang (ORCID: https://orcid.org/0000-0002-1646-063X)
- Chunliang Li (ORCID: https://orcid.org/0000-0002-5938-5510)
- Vivek Choudhary
Institutions
- St. Jude Children's Research Hospital (US)
Publication Details
- Journal
- Science Advances
- Published
- 2026-10-28
- DOI
- https://doi.org/10.1126/sciadv.aeh9188
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- American Lebanese Syrian Associated Charities
- National Institutes of Health
- National Cancer Institute