The αE(CD103)β7 integrin interacts with oral and skin keratinocytes in an E-cadherin-independent manner*

Abstract

SummaryThe integrin aE(CD103)b7 (aEb7) is expressed by intraepithelial lymphocytes, dendritic cells and regulatory T cells. It plays an important role in the mucosal immune system by retaining lymphocytes within the epithelium and is involved in graft rejection, immunity against tumours and the generation of gut-homing effector cells. In gut and breast, the ligand for aEb7 is E-cadherin but in human oral mucosa and skin, there is evidence that lymphocytes use an alternative, unknown, ligand. In the present study, the I domain of the human aE subunit, which contains the E-cadherin-binding site, was locked in a highly active, 'open' and an inactive, 'closed' conformation by the introduction of disulphide bonds and these domains were expressed as IgG Fc fusion proteins. aE fusion proteins recognize E-cadherin, the only known ligand for aEb7. This interaction was inhibited by an antibody that blocks the aE-binding site on E-cadherin and by the omission of Mn 2+ , which is essential for integrin function in vitro. The locked 'open' conformation of aE adhered to human oral and skin keratinocytes, including the E-cadherin-negative H376 cell line, and this was not inhibited by blocking antibody against the aEb7-binding site on E-cadherin, providing further evidence for the existence of an alternative ligand for aEb7 in skin and oral mucosa. The interaction with E-cadherin and the alternative ligand was Mn 2+ dependent and mediated by the metal ion-dependent coordination site (MIDAS) of the locked 'open' aE I domain, independently of the b7 subunit.

The Structure of the Human Vaginal Stratum Corneum and its Role in Immune Defense

“…We and others have observed that leukocytes can penetrate and traverse the SC following placement in the vaginal lumen (apical-to-basal infiltration), suggesting a mechanism for cell-associated HIV transmission via infected cells deposited in semen 31–33 . Leukocytes may freely move through this cell layer because the epithelial cells lack e-cadherin 16 and possibly other adhesive molecules that retain and integrate immune cells in mucosal epithelia 34,35 . It is currently unknown to what extent leukocytes actively perform immunosurveillance of this cell layer.…”

Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections

“…The α E β 7 integrin has been associated with lung, gut, and skin homing, whereas the α 4 β 7 integrin has been associated with gut homing (21). Skinhoming α E + β 7 + T cells also express CLA (38). We therefore investigated the expression of the α E β 7 integrin in the whole CD3 + T cell compartment, in the CD3 + CLA + T cell compartment ( Figure 3D, Supplemental Figure 7, C and F, and Supplemental Figure 8D), and in the various naive and memory T cell compartments of the patients' PBMCs (Supplemental Figure 9, C and D).…”

β7 Integrin Controls Mast Cell Recruitment, whereas αE Integrin Modulates the Number and Function of CD8+ T Cells in Immune Complex–Mediated Tissue Injury

“…In addition to E-cadherin, aEb7 integrin is known to have two other ligands. One is a ligand expressed on microvascular endothelial cells (24), whereas the other is expressed on oral and skin keratinocytes (25). Details of these two ligands are yet to be clarified.…”