Critical role of the fifth domain of E-cadherin for heterophilic adhesion with α_Eβ₇, but not for homophilic adhesion

The integrin α_Eβ₇ is expressed on intestinal intraepithelial T lymphocytes and CD8⁺ T lymphocytes in inflammatory lesions near epithelial cells. Adhesion between α_Eβ₇⁺ T and epithelial cells is mediated by the adhesive interaction of α_Eβ₇ and E-cadherin; this interaction plays a key role in the damage of target epithelia. To explore the structure-function relationship of the heterophilic adhesive interaction between E-cadherin and α_Eβ ₇, we performed cell aggregation assays using L cells transfected with an extracellular domain-deletion mutant of E-cadherin. In homophilic adhesion assays, L cells transfected with wild-type or a domain 5-deficient mutant formed aggregates, whereas transfectants with domain 1-, 2-, 3-, or 4-deficient mutants did not. These results indicate that not only domain 1, but domains 2, 3, and 4 are involved in homophilic adhesion. When α_Eβ₇⁺ K562 cells were incubated with L cells expressing the wild type, 23% of the resulting cell aggregates consisted of α_Eβ₇⁺ K562 cells. In contrast, the binding of α_Eβ₇⁺ K562 cells to L cells expressing a domain 5-deficient mutant was significantly decreased, with α_Eβ₇⁺ K562 cells accounting for only 4% of the cell aggregates, while homophilic adhesion was completely preserved. These results suggest that domain 5 is involved in heterophilic adhesion with α_Eβ₇, but not in homophilic adhesion, leading to the hypothesis that the fifth domain of E-cadherin may play a critical role in the regulation of heterophilic adhesion to α_Eβ₇ and may be a potential target for treatments altering the adhesion of α_Eβ₇ ⁺ T cells to epithelial cells in inflammatory epithelial diseases.