The alpha E(CD103) beta 7 integrin interacts with oral and skin keratinocytes in an E-cadherin-independent manner

The integrin alpha E(CD103) beta 7 ( alpha E beta 7) 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 alpha E beta 7 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 alpha E 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. alpha E fusion proteins recognize E-cadherin, the only known ligand for alpha E beta 7. This interaction was inhibited by an antibody that blocks the alpha E-binding site on E-cadherin and by the omission of Mn2+, which is essential for integrin function in vitro. The locked 'open' conformation of alpha E 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 alpha E beta 7-binding site on E-cadherin, providing further evidence for the existence of an alternative ligand for alpha E beta 7 in skin and oral mucosa. The interaction with E-cadherin and the alternative ligand was Mn2+ dependent and mediated by the metal ion-dependent coordination site (MIDAS) of the locked 'open' alpha E I domain, independently of the beta 7 subunit.