Aberrant activation of integrin alpha4beta7 suppresses lymphocyte migration to the gut.
Integrin adhesion molecules mediate lymphocyte migration and homing to normal and inflamed tissues. While the ligand-binding activity of integrins is known to be modulated by conformational changes, little is known about how the appropriate balance of integrin adhesiveness is maintained in order to optimize the migratory capacity of lymphocytes in vivo. In this study we examined the regulation of the gut homing receptor alpha4beta7 integrin by manipulating at the germline level an integrin regulatory domain known as adjacent to metal ion-dependent adhesion site (ADMIDAS). ADMIDAS normally serves to raise the activation threshold of alpha4beta7, thereby stabilizing it in the default nonadhesive state. Lymphocytes from knockin beta7 (D146A) mice, which harbor a disrupted ADMIDAS, not only expressed an alpha4beta7 integrin that persistently adhered to mucosal addressin cell adhesion molecule-1 (MAdCAM-1), but also exhibited perturbed cell migration along MAdCAM-1 substrates resulting from improper de-adhesion of the lymphocyte trailing edge. In vivo, aberrantly activated alpha4beta7 enhanced adhesion to Peyer's patch venules, but suppressed lymphocyte homing to the gut, diminishing the capacity of T cells to induce colitis. Our results underscore the importance of a proper balance in the adhesion and de-adhesion of the alpha4beta7 integrin, both for lymphocyte trafficking to the gut and for colitis progression.
Park
Eun Jeong
EJ
CBR Institute for Biomedical Research, Boston, Massachusetts 02115, USA.
Mora
J Rodrigo
JR
Carman
Christopher V
CV
Chen
JianFeng
J
Sasaki
Yoshiteru
Y
Cheng
Guiying
G
von Andrian
Ulrich H
UH
Shimaoka
Motomu
M
D020816:Amino Acid Motifs; D000818:Animals; D001224:Aspartic Acid / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D015415:Biomarkers; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology*; D008214:Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009088:Mucoproteins; D009154:Mutation / Q000235:genetics; D011485:Protein Binding