Dual functions of Rap1 are crucial for T-cell homeostasis and prevention of spontaneous colitis

Sayaka Ishihara, Akihiko Nishikimi, Eiji Umemoto, Masayuki Miyasaka, Makoto Saegusa and Koko Katagiri ()
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Sayaka Ishihara: School of Science, Kitasato University
Akihiko Nishikimi: School of Science, Kitasato University
Eiji Umemoto: Laboratory of Immune Regulation, Osaka University Graduate School of Medicine
Masayuki Miyasaka: Interdisciplinary Program for Biomedical Sciences, Institute for Academic Initiatives, Osaka University
Makoto Saegusa: School of Medicine, Kitasato University
Koko Katagiri: School of Science, Kitasato University

Nature Communications, 2015, vol. 6, issue 1, 1-16

Abstract: Abstract Rap1-GTP activates leukocyte function-associated antigen-1 (LFA-1) to induce arrest on the high endothelial venule (HEV). Here we show that Rap1-GDP restrains rolling behaviours of T cells on the peripheral lymph node addressin (PNAd), P-selectin and mucosal addressin cell adhesion molecule-1 (MadCAM-1) by inhibiting tether formation. Consequently, Rap1 deficiency impairs homing of naive T cells to peripheral lymph nodes, but accelerates homing of TH17 and TH1 cells to the colon, resulting in spontaneous colitis with tumours. Rap1-GDP associates with and activates lymphocyte-oriented kinase, which phosphorylates ERM (ezrin, radixin and moesin) in resting T cells. Phosphomimetic ezrin reduces the rolling of Rap1-deficient cells, and thereby decreases their homing into the colon. On the other hand, chemokines activate Rap1 at the plasma membrane within seconds, and Rap1-GTP binds to filamins, which diminishes its association with the β2 chain of LFA-1 and results in LFA-1 activation. This Rap1-dependent regulation of T-cell circulation prevents the onset of colitis.

Date: 2015
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DOI: 10.1038/ncomms9982

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