Abstract
Intraepithelial lymphocytes (IELs) of the small intestine are intimately associated with the epithelial cells. Yet, the factors controlling their migration and interaction dynamics are poorly understood. We demonstrate that GPR55, a receptor that mediates migration inhibition in response to lysophosphatidylinositol (LPI), negatively regulates T cell receptor γδ (TCRγδ) IEL accumulation in the small intestine. Intravital imaging studies show that GPR55-deficient IELs migrate faster and interact more extensively with epithelial cells. GPR55 also negatively regulates T cell homing to the small intestine and γδT cell egress from Peyer's patches. GPR55 deficiency or short-term antagonist treatment protects from nonsteroidal anti-inflammatory drug-induced increases in intestinal permeability. These findings identify a migration-inhibitory receptor that restrains IEL-epithelial cell cross-talk and show that antagonism of this receptor can protect from intestinal barrier dysfunction.