GPCR-Gα13 signaling regulates survival of intestinal intraepithelial CD8 lymphocytes through migration to cytokine-rich niches

SUMMARY Intestinal intraepithelial lymphocytes (IEL), including conventional CD8αβ T resident memory (Trm) cells and unconventional CD8αα T cells, promote tissue integrity. Here, we studied the G-protein coupled receptor signals regulating IEL positioning, homeostasis, and function. Deficiency in heterotrimeric G-protein subunit Gα13 or its effector Arhgef1 caused an intestine-specific loss of all types of CD8 + TCRαβ and TCRγδ IEL. Gα13-deficient IEL exhibited restricted intraepithelial movement and impaired maturation. Induction of intestinal CD8αβ + Trm upon infection was intact in the absence of Gα13-signaling, but the cells had poor access to the villous niche and defective survival that could be rescued by increasing TGFβ + or interleukin (IL)15. In vivo CRISPR/Cas9 screening identified GPR132 as a Gα13-coupled receptor that regulates CD8αβ + IEL homeostasis and migration to lysophosphatidylcholine. Mice bearing Gα13-deficient T cells suffered more severe colitis and increased colorectal tumor growth. The selective requirement for Gα13-signaling for IEL positioning and survival in the villous niche has implications for therapeutic intervention.