Intestinal intraepithelial lymphocyte migration and tissue homeostasis are dictated by Gα13

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.

doi:10.64898/2026.03.01.708910

bioRxiv · 10.64898/2026.03.01.708910

Intestinal intraepithelial lymphocyte migration and tissue homeostasis are dictated by Gα13

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.

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Abstract

Intestinal intraepithelial lymphocytes (IEL), including conventional CD8{beta} T resident memory (Trm) cells and unconventional CD8 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 G13 or its effector Arhgef1 caused an intestine-specific loss of all types of CD8+ TCR{beta} and TCR{gamma}{delta} IEL. G13-deficient IEL exhibited restricted intraepithelial movement and impaired maturation. Induction of intestinal CD8{beta}+ Trm upon infection was intact in the absence of G13-signaling, but the cells had poor access to the villous niche and defective survival that could be rescued by increasing TGF{beta}+ or interleukin (IL)15. In vivo CRISPR/Cas9 screening identified GPR132 as a G13-coupled receptor that regulates CD8{beta}+ IEL homeostasis and migration to lysophosphatidylcholine. Mice bearing G13-deficient T cells suffered more severe colitis and increased colorectal tumor growth. The selective requirement for G13-signaling for IEL positioning and survival in the villous niche has implications for therapeutic intervention.

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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.. 2026-03-03. Intestinal intraepithelial lymphocyte migration and tissue homeostasis are dictated by Gα13. https://doi.org/10.64898/2026.03.01.708910

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