GPR15-guided CD8+ T regulatory cells control intestinal inflammation

作者：Jing Cui, Zuojia Chen, Yan Cheng, Jia Nie, Maria H Zhu, Xiang Chen, Samuel Chauvin, Wiem Lassoued, Can Liu, Kartika Padhan, Jian Song, Joy A. Pai, Borja Ocón, Yifan Yang, Yikun Yao, Ann Y. Park, Justin Q. Gabrielski, Lixin Zheng, Ping Jiang, Yu Zhang, Huie Jing, Leilei Xu, Vicky Chen, Brent A. Calabresi, Stefania Pittaluga, David E. Kleiner, Clifton L. Dalgard, Sinan Sari, Salim Can, Elif Karakoc-Aydiner, Safa Baris, Baran Erman, Michael Field, Jocelyn A. Silvester, Gwen Saccocia, Eman K. Buhamrah, Khaled Husain, Zahra Chavoshzadeh, Nima Rezaei, A Islek, Hasan Baş, Fatma Dereli Devrez, Rafah Mackeh, Ivan J. Fuss, Daniel S Reich, Shania Bailey, Houssein Abdul Sater, James L. Gulley, Juraj Kabát, Margery Smelkinson, Sundar Ganesan, Z X Chen, Peter C. Grayson, Neelam Redekar, Justin Lack, Zhiyong Lu, Bernice Lo, Hassan Abolhassani, Ahmet Özen, Athos Bousvaros, Scott B. Snapper, Eugene C. Butcher, Juan Ravell, Remy Bosselut, Helen Su, Chuan Wu, Michael J. Lenardo · 发表于：Nature · 年份：2026 · DOI：10.1038/s41586-026-10749-4 · 研究领域：T-cell and B-cell Immunology、Chemokine receptors and signaling、TGF-β signaling in diseases

Abstract Inflammatory bowel disease (IBD) causes chronic suffering from gastrointestinal inflammation and dysfunction that can progress to colon cancer 1,2 . The prevalence of the disease is increasing, and there is an urgent need to better understand its pathogenic mechanisms to improve treatment. We show that GPR15—a G-protein-coupled receptor expressed in immune cells and described previously as an entry co-factor for human and simian immunodeficiency viruses 3 —is a marker and homing receptor for a subset of intramucosal GPR15-guided regulatory CD8 + T lymphocytes (CD8 + T IGR cells). Deleterious GPR15 gene variants in humans cause defective homing of CD8 + T IGR cells and are associated with severe early-onset IBD. Moreover, CD8 + T IGR cells are reduced in the intestinal mucosa of individuals with sporadic IBD. In mice, GPR15 deficiency impairs colonic homing of CD8 + T IGR cells, leading to accumulation of inflammatory macrophages and increased susceptibility to colitis. CD8 + T IGR cells potently kill macrophages activated by intestinal damage or disease using Fas ligand and TNF-related weak inducer of apoptosis (TWEAK). The identification of CD8 + T IGR cells yields new insights into organ-specific immune regulation and potential therapeutics for IBD.