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Original Article

Molecular Basis for Leukocyte Integrin _Eβ₇ Adhesion to Epithelial (E)-Cadherin

^a From the Lymphocyte Biology Section, Division of Rheumatology, Immunology and Allergy, the
^b Renal Division, Department of Medicine, Brigham and Women's Hospital,
^c Dana-Farber Cancer Institute and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115
Lymphocyte Biology Section, Division of Rheumatology, Immunology and Allergy, Department of Internal Medicine, Bringham and Women's Hospital, One Jimmy Fund Way, Smith Bldg., Rm. 552, Boston, MA 02115.617-525-1010617-525-1000

mbrenner{at}rics.bwh.harvard.edu

Cadherins are expressed in tissue-restricted patterns and typically mediate homophilic adhesion. Cadherins also mediate lymphocyte adhesion, providing the opportunity for lymphocyte attachment to parenchymal cells. The best characterized example of lymphocyte adhesion to a tissue-specific cell adhesion molecule, as opposed to a vascular endothelial adhesion molecule, is the interaction between integrin _Eβ₇ on intraepithelial lymphocytes and E-cadherin on epithelial cells. However, the molecular basis for an integrin–cadherin interaction is not well defined. Realization that the cadherin domain adopts a topology similar to the immunoglobulin (Ig) fold suggested that integrin recognition of E-cadherin might be similar to recognition of Ig superfamily ligands. Thus, we modeled domain 1 of human E-cadherin and studied the role of solvent-exposed loops that connect Ig-like core-forming β strands. Mutational analyses localized the integrin _Eβ₇ recognition site to the top of domain 1 at the face formed by the BC and FG loops, a site distinct from the region recognized in intercellular adhesion molecule (ICAM)-1, -2, and -3, mucosal addressin cell adhesion molecule 1 (MAdCAM-1), vascular cell adhesion molecule 1 (VCAM-1), and fibronectin by their integrin ligands. Moreover, the integrin _Eβ₇ binding site is distinct from the homophilic binding site on E-cadherin. These studies provide a conceptual basis for integrin–cadherin binding and extend the model that an Ig-like fold can serve as a scaffold for recognition.

Key Words: cadherins • integrins • cell adhesion • T lymphocytes • protein binding

Abbreviations used in this paper: E, epithelial; FBS, fetal bovine serum; HBS, Hepes-buffered saline; HEK, human embryonic kidney; IEL, intraepithelial lymphocyte; IgSF, Ig superfamily; ICAM, intercellular adhesion molecule; K562-_Eβ₇, K562 cells stably transfected with _Eβ₇; MAdCAM-1, mucosal addressin cell adhesion molecule 1; N, neural; P, placental; TBS, Tris-buffered saline; VCAM-1, vascular cell adhesion molecule 1.

© 2000 The Rockefeller University Press

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