GPCR-Gα13 Signaling Regulates Survival of Intestinal Intraepithelial CD8+ Lymphocytes Through Migration to Cytokine-Rich Niches

Intestinal intraepithelial lymphocytes (IELs), 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 IELs. Gα13-deficient IELs exhibited restricted intraepithelial movement and impaired maturation. Induction of intestinal CD8αβ+ Trm cells 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 TGF-β 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.