GPR55 regulates intraepithelial lymphocyte migration dynamics and susceptibility to intestinal damage

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Science Immunology  08 Dec 2017:
Vol. 2, Issue 18, eaao1135
DOI: 10.1126/sciimmunol.aao1135

Restraining intestinal lymphocyte migration

Migration of intraepithelial lymphocytes (IELs) is controlled by several factors. Here, Sumida et al. report that G protein–coupled receptor 55 (GPR55) negatively regulates IEL migration in the small intestine. The authors show that lysophosphatidylinositols (LPIs), a class of ligands active on GPR55 in vitro, are abundant in the small intestine. In response to indomethacin-induced intestinal leakage, the authors documented that GPR55-deficient mice recruited greater numbers of IELs and were more resistant to intestinal injury. In addition to establishing the role of GPR55 in IEL migration, the study underscores the importance of IELs in maintaining the integrity of the gut epithelial barrier.


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.

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