Aberrant activation of integrin α4β7 suppresses lymphocyte migration to the gut
Eun Jeong Park, J. Rodrigo Mora, Christopher V. Carman, JianFeng Chen, Yoshiteru Sasaki, Guiying Cheng, Ulrich H. von Andrian, Motomu Shimaoka
Eun Jeong Park, J. Rodrigo Mora, Christopher V. Carman, JianFeng Chen, Yoshiteru Sasaki, Guiying Cheng, Ulrich H. von Andrian, Motomu Shimaoka
View: Text | PDF
Research Article

Aberrant activation of integrin α4β7 suppresses lymphocyte migration to the gut

Abstract

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 α4β7 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 α4β7, thereby stabilizing it in the default nonadhesive state. Lymphocytes from knockin β7 (D146A) mice, which harbor a disrupted ADMIDAS, not only expressed an α4β7 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 α4β7 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 α4β7 integrin, both for lymphocyte trafficking to the gut and for colitis progression.

Authors

Eun Jeong Park, J. Rodrigo Mora, Christopher V. Carman, JianFeng Chen, Yoshiteru Sasaki, Guiying Cheng, Ulrich H. von Andrian, Motomu Shimaoka

×

Figure 3

Expression of integrins and activation markers in β7 (D146A) mice.

Options: View larger image (or click on image) Download as PowerPoint
Expression of integrins and activation markers in β7 (D146A) mice. ...
(A) Cell surface expression of integrins on WT and β7 (D146A) KI lymphocytes from the SP and from SI-IEL and SI-LPL compartments. (B) Cell surface expression of activation markers on lymphocytes from SP. (C) mRNA expression of β7 integrins in splenocytes. Real-time quantitative RT-PCR was performed by iCycler (Bio-Rad). The mRNA expression of the β7 integrin was normalized to that of GAPDH. Dots represent 3 independent data sets; bars denote mean values. (D) Total (cell surface plus intracellular) protein expression of β7 integrins in splenocytes. Total expression was examined by immunofluorescent flow cytometry using permeabilized cells. (E) Effects of a proteasome inhibitor on the cell surface expression of integrins. WT and KI splenocytes were treated for 8 hours with epoxomicin (0.5 μM) in the presence of PMA (20 nM) and ionomycin (1 μM). Surface expression of αL and β7 integrins was examined by flow cytometry. (F) Effects of CD3/CD28/RA treatment on the expression of cell surface receptors. Splenocytes were stimulated with mAbs to CD3 and CD28 for 2 days and treated for 3 days with RA in the absence of mAb stimulation. (A, B, D, and F) Numbers denote mean fluorescent intensity (MFI). Binding of isotype control antibodies is shown with dashed lines. (E) Numbers denoting MFI values for vehicle-treated (dashed lines) and epoxomicin-treated (solid lines) samples are shown with and without parentheses, respectively.