title: The αE(CD103)β7 integrin interacts with oral and skin keratinocytes in an E-cadherin-independent manner*.
abstract: The integrin αE(CD103)β7 (αEβ7) 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 αEβ7 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 αE 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. αE fusion proteins recognize E-cadherin, the only known ligand for αEβ7. This interaction was inhibited by an antibody that blocks the αE-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 αE 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 αEβ7-binding site on E-cadherin, providing further evidence for the existence of an alternative ligand for αEβ7 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'αE I domain, independently of the β7 subunit.
authors.affiliation: Unit of Oral and Maxillofacial Pathology, School of Clinical Dentistry, University of Sheffield, Sheffield Babraham Institute, Cambridge, UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Jenkinson
authors.forename: Simon A
authors.initials: SA
authors.lastname: Whawell
authors.forename: Brenka M
authors.initials: BM
authors.lastname: Swales
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Corps
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Kilshaw
authors.forename: Paula M
authors.initials: PM
authors.lastname: Farthing
mesh_terms: D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D015820:Cadherins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D006801:Humans; D018928:Immunity, Mucosal; D039001:Integrin alpha Chains / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D039641:Integrin beta Chains / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D008024:Ligands; D009061:Mouth Mucosa / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D039001:Integrin alpha Chains; D039641:Integrin beta Chains; D008024:Ligands; D011993:Recombinant Fusion Proteins; C091367:alpha E integrins; C091368:integrin beta7