Earley, Z. M.; Rao, A.; Knopper, K.; Peng, F.; Qiu, L.; Jo, N.; Lisicka, W.; Taglinao, H.; An, J.; Xu, Y.; Yang, L. V.; Liu, D.; Looney, M. R.; Cyster, J. G.

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 G13 or effector Arhgef1 causes a loss of CD8 and CD8{beta} IEL. Following G13 ablation, IEL reduce migration speed prior to undergoing cell death. Induction of CD8 IEL by Listeria monocytogenes is intact but the cells fail to distribute along the villi and quickly die. TGF{beta} gain-of-function rescues Arhgef1-deficient CD8 cell numbers. CRISPR screening identifies a role for G13-coupled GPR132 in IEL homeostasis. T cell G13-deficient mice suffer more severe colitis and colorectal tumor growth. In summary, we identify G13 as an essential signaling node in {beta} and {gamma}{delta} CD8 IEL and we propose G13-guided IEL positioning in the villous niche is required for receipt of signals, including TGF{beta}, for their maturation, survival and function.