Mcl-1 is a member of the

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.