GPR18 is required for a normal CD8αα intestinal intraepithelial lymphocyte compartment

Intraepithelial lymphocytes (IELs) play an important role in maintaining the physiology of the small intestine. The majority of mouse IELs express CD8 alpha alpha and are either gamma delta or alpha beta T cells. Although the development and homing of CD8 alpha alpha IELs have been studied in some detail, the factors controlling their homeostasis and positioning are incompletely understood. Here we demonstrate that G protein-coupled receptor 18 (GPR18) is abundantly expressed in CD8 alpha alpha IELs and that mice lacking this orphan receptor have reduced numbers of gamma delta T IELs. Mixed bone marrow chimera experiments reveal a markedly reduced contribution of GPR18-deficient cells to the CD8 alpha alpha IEL compartment and a reduction in the CD8 alpha beta T cell subset. These defects could be rescued by transduction with a GPR18-expressing retrovirus. The GPR18-deficient gamma delta T IELs that remained in mixed chimeras had elevated Thy1, and there were less granzyme B+ and V gamma 7(+) cells, indicating a greater reduction in effector-type cells. Flow cytometric analysis indicated GPR18 deficiency more strongly affected the CD8 alpha alpha cells in the intraepithelial compared with the adjacent lamina propria compartment. These findings establish a requirement for GPR18 in CD8 alpha alpha and CD8 alpha beta IELs, and we suggest the receptor has a role in augmenting the accumulation of CD8 T cells in the intraepithelial versus lamina propria compartment.