GPR15-guided CD8⁺ T regulatory cells control intestinal inflammation.

Area of Science:

• Immunology
• Gastroenterology
• Molecular Biology

Background:

• Inflammatory bowel disease (IBD) is a growing global health concern characterized by chronic gastrointestinal inflammation.
• Understanding the molecular mechanisms underlying IBD pathogenesis is critical for developing effective treatments.
• Regulatory T cells play a key role in maintaining gut homeostasis and preventing excessive inflammation.

Purpose of the Study:

• To investigate the role of G protein-coupled receptor 15 (GPR15) in the context of inflammatory bowel disease.
• To identify novel immune cell subsets involved in IBD pathogenesis and regulation.
• To explore GPR15 as a potential therapeutic target for IBD.

Main Methods:

• Utilized genetic analysis to identify deleterious GPR15 variants in IBD patients.
• Employed flow cytometry and immunohistochemistry to characterize immune cell populations in intestinal mucosa.
• Conducted mouse models of colitis to assess the functional role of GPR15 and GPR15-guided T cells.

Main Results:

• Identified GPR15 as a specific marker and homing receptor for a subset of regulatory CD8+ T lymphocytes (CD8+ TIGR) in the gut mucosa.
• Demonstrated that deleterious GPR15 variants are associated with severe early-onset IBD due to defective CD8+ TIGR cell homing.
• Observed reduced CD8+ TIGR cell numbers in the intestinal mucosa of sporadic IBD patients and showed GPR15 deficiency exacerbates colitis in mice.

Conclusions:

• GPR15 is essential for the homing of CD8+ TIGR cells to the intestinal mucosa, playing a critical role in immune regulation.
• Defects in GPR15-mediated homing contribute to the pathogenesis of inflammatory bowel disease.
• CD8+ TIGR cells, through mechanisms involving FasL and TWEAK, offer potential therapeutic strategies for IBD.