Role of the mucosal integrin alpha(E)(CD103)beta(7) in tissue-restricted cytotoxicity.
The effectiveness of lung transplantation is marred by the relatively high incidence of rejection. The lung normally contains a large population of lymphocytes in contact with the airway epithelium, a proportion of which expresses the mucosal integrin, alpha(E)(CD103)beta(7). This integrin is not a homing receptor, but is thought to retain lymphocytes at the epithelial surface. Following transplantation, a population of 'tissue-restricted' cytotoxic T cells (CTL) have been identified which have the ability to lyse epithelial cells, but not major histocompatibility complex (MHC)-identical splenic cells. We tested the hypothesis that expression of the mucosal integrin confers the ability of CTL to target and destroy e-cadherin expressing targets. Immunohistochemical and flow cytometric analyses were used to demonstrate the relevance of this model to human lung. Allo-activated CTL were generated in mixed leucocyte reactions and CD103 expression up-regulated by the addition of transforming growth factor (TGF)-beta. The functional effect of CD103 expression was investigated in (51)Cr-release assays using e-cadherin-expressing transfectant targets. Human lung epithelial cells express e-cadherin and one-third of intraepithelial lymphocytes (IEL) expressed CD103. Allo-activated and bronchoalveolar lavage (BAL) lymphocytes express more CD103 than those in blood. Transfection of e-cadherin into murine fibroblasts conferred susceptibility to lysis by alpha(E)beta(7)-expressing CTL which could be blocked by specific monoclonal antibodies to CD103 and e-cadherin. CD103 functions to conjugate CTL effectors to e-cadherin-expressing targets and thereby facilitates cellular cytotoxicity. E-cadherin is expressed prominently by epithelial cells in the lung, enabling CTL to target them for destruction.
Smyth
L J C
LJ
Institute of Pharmacy, Chemistry and Biomedical Sciences, University of Sunderland, UK.
Kirby
J A
JA
Cunningham
A C
AC
D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000276:immunology; D006801:Humans; D018928:Immunity, Mucosal / Q000276:immunology; D016130:Immunophenotyping; D039001:Integrin alpha Chains / Q000276:immunology* / Q000378:metabolism; D008168:Lung / Q000276:immunology; D016040:Lung Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008875:Middle Aged; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection
D015703:Antigens, CD; D015820:Cadherins; D039001:Integrin alpha Chains; C091367:alpha E integrins