Role of T cell homing receptor GPR15 in colitis: mouse versus man

▸ Nguyen LP, Pan J, Dinh TT, et al. Role and species-specific expression of colon T cell homing receptor GPR15 in colitis. Nat Immunol 2015;16:207–13.

Recruitment of lymphocytes from the circulation maintains immune homeostasis in the gut while also playing a role in appropriate inflammatory response. This recruitment process is mediated by adhesion and chemoattractant receptors. GPR15 is an HIV coreceptor and an orphan G-protein-coupled receptor with structural homology to known lymphocyte trafficking receptors. Recently, GPR15 was implicated in colon homing of regulatory T (T_reg) cells in the mouse; however, its role in effector T cell trafficking and function is unclear. In this study by Nguyen and colleagues, the expression and function of GPR15 on effector T cells in mice and humans was investigated. The authors showed that GPR15 is important for TH1 and TH17 effector cell localisation to the mouse colon. The CD45RB^hi CD4⁺ T cell transfer model of colitis, which is dependent on effector T cell expression of intestinal trafficking receptors, was used to determine the importance of GPR15 in colon inflammation. Gpr15-deficient cells were unable to induce colitis, thus revealing a role of GPR15 in the colon trafficking of pathogenic proinflammatory T cells. To determine the relevance of mouse studies to humans, GPR15 expression by colon CD4⁺ T cells from individuals with UC or Crohn's disease and in colons from individuals without UC that included healthy or normal margins of caecal or colorectal adenocarcinomas was investigated. GPR15 was expressed by effector cells, including pathogenic TH2 cells in UC, but was expressed minimally or not at all by colon T_reg cells. The differences in T_reg cells compared with T cell effector cell expression of GPR15 between mice and humans were attributed to interspecies differences in binding of transcriptional regulators to GPR15 …