| First Author | Ishihara S | Year | 2015 |
| Journal | Nat Commun | Volume | 6 |
| Pages | 8982 | PubMed ID | 26634692 |
| Mgi Jnum | J:228314 | Mgi Id | MGI:5706682 |
| Doi | 10.1038/ncomms9982 | Citation | Ishihara S, et al. (2015) Dual functions of Rap1 are crucial for T-cell homeostasis and prevention of spontaneous colitis. Nat Commun 6:8982 |
| abstractText | 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 beta2 chain of LFA-1 and results in LFA-1 activation. This Rap1-dependent regulation of T-cell circulation prevents the onset of colitis. |
