Wdr82-COMPASS coordinates Foxp3 and TCR signaling to sustain Treg cell control of microbiota-driven intestinal inflammation
6 affiliations
- 1Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
- 2Center for Applied Bioinformatics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
- 3Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
- 4Center for Advanced Genome Engineering, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
- 5Center for Proteomics and Metabolomics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
- 6Department of Tumor Cell Biology, 4, Memphis, TN 38105, USA.
Abstract
Regulatory T cells (Treg cells) maintain immune tolerance, but how broadly acting epigenetic pathways are selectively used by Treg cells versus conventional T cells (Tconv 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 Treg 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 Tconv cell programs. This pathology is prevented by microbiome depletion or transfer of wild-type Treg cells, indicating a primary defect in Treg cell-mediated tolerance. Mechanistically, Wdr82/COMPASS promotes Foxp3 induction, maintains H3K4me3 and chromatin accessibility at Treg cell-associated genes, and restrains effector programs within the Treg 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 Treg cell control of microbiota-driven intestinal inflammation.
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BibTeX
@article{huang2026wdr82compass,
title = {{Wdr82-COMPASS coordinates Foxp3 and TCR signaling to sustain Treg cell control of microbiota-driven intestinal inflammation}},
author = {Wenjun Huang and Jun Li and Minghong He and Beisi Xu and Wojciech Rosikiewicz and Xiaolei Hao and Menglin Jiang and Lu Bai and Siwei Zhang and Lei Li and Wenjie Qi and Vivek Choudhary and Min-Jhen Jheng and Ti-Cheng Chang and Laura J. Janke and Shondra M. Pruett-Miller and Kiran Kodali and Zuo-Fei Yuan and Anthony A. High and Hongjian Jin and Chunliang Li and Yongqiang Feng},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aeh9188},
url = {https://www.science.org/doi/abs/10.1126/sciadv.aeh9188},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Wdr82-COMPASS coordinates Foxp3 and TCR signaling to sustain Treg cell control of microbiota-driven intestinal inflammation
AU - Wenjun Huang
AU - Jun Li
AU - Minghong He
AU - Beisi Xu
AU - Wojciech Rosikiewicz
AU - Xiaolei Hao
AU - Menglin Jiang
AU - Lu Bai
AU - Siwei Zhang
AU - Lei Li
AU - Wenjie Qi
AU - Vivek Choudhary
AU - Min-Jhen Jheng
AU - Ti-Cheng Chang
AU - Laura J. Janke
AU - Shondra M. Pruett-Miller
AU - Kiran Kodali
AU - Zuo-Fei Yuan
AU - Anthony A. High
AU - Hongjian Jin
AU - Chunliang Li
AU - Yongqiang Feng
PY - 2026
DA - 2026/10/28
JO - Science Advances
DO - 10.1126/sciadv.aeh9188
UR - https://www.science.org/doi/abs/10.1126/sciadv.aeh9188
AB - Regulatory T cells (Treg cells) maintain immune tolerance, but how broadly acting epigenetic pathways are selectively used by Treg cells versus conventional T cells (Tconv 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 Treg 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 Tconv cell programs. This pathology is prevented by microbiome depletion or transfer of wild-type Treg cells, indicating a primary defect in Treg cell-mediated tolerance. Mechanistically, Wdr82/COMPASS promotes Foxp3 induction, maintains H3K4me3 and chromatin accessibility at Treg cell-associated genes, and restrains effector programs within the Treg 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 Treg cell control of microbiota-driven intestinal inflammation.
SN - 2375-2548
ER -