GPR15-guided CD8+ T regulatory cells control intestinal inflammation
Abstract
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.
Article Details
Authors (67)
Jing Cui
Zuojia Chen
Yan H. Cheng
Jia Nie
Maria H. Zhu
Chen Xiang
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 Du Jiang
Yu Zhang
Xiangya Hospital, Central South University Changsha China
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
Ali İşlek
Hasan Baş
Fatma Dereli Devrez
Rafah Mackeh
Ivan J. Fuss
Daniel S. Reich
Shania Bailey
Houssein Abdul Sater
James L. Gulley
Juraj Kabat
Margery Smelkinson
Sundar Ganesan
Zhenghao Chen
Peter C. Grayson
Neelam Redekar
Justin Lack
Zhiyong Lu
Bernice Lo
Hassan Abolhassani
Ahmet Ozen
Athos Bousvaros
Scott B. Snapper
Eugene C. Butcher
Juan Ravell
Rémy Bosselut
Helen C. Su
Chuan Wu
Michael J. Lenardo