Intestinal intraepithelial lymphocyte migration and tissue homeostasis are dictated by Gα13

The intestinal barrier harbors numerous intraepithelial lymphocytes (IEL) that promote tissue integrity and whose dysfunction contributes to disease. The signals regulating IEL dynamics are incompletely understood. Here we show that deficiency in heterotrimeric G-protein subunit Gα13 or effector Arhgef1 causes a loss of CD8αα and CD8αβ IEL. Following Gα13 ablation, IEL reduce migration speed prior to undergoing cell death. Induction of CD8αβ IEL by Listeria monocytogenes is intact but the cells fail to distribute along the villi and quickly die. TGFβ gain-of-function rescues Arhgef1-deficient CD8αβ cell numbers. CRISPR screening identifies a role for Gα13-coupled GPR132 in IEL homeostasis. T cell Gα13-deficient mice suffer more severe colitis and colorectal tumor growth. In summary, we identify Gα13 as an essential signaling node in αβ and γδ CD8 IEL and we propose Gα13-guided IEL positioning in the villous niche is required for receipt of signals, including TGFβ, for their maturation, survival and function.