Role for E-Cadherin as an Inhibitory Receptor on Epidermal γδ T Cells

E-cadherin is a homophilic adhesion molecule that maintains homotypic intercellular adhesion between epithelial cells such as epidermal keratinocytes. E-cadherin is also expressed on resident murine epidermal gamma delta T cells, known as dendritic epidermal T cells (DETCs), but they express another receptor for E-cadherin, alpha(E)(CD103)beta(7) integrin, as well. In this study, we analyzed functional differences between E-cadherin-mediated homophilic binding and heterophilic binding of alpha(E)beta(7) integrin to E-cadherin in heterotypic intercellular adhesion of DETCs to keratinocytes. E-cadherin, but not alpha(E)beta(7) integrin, was downregulated on activation of DETCs in vivo and in vitro. Short-term (1-h) adhesion of DETCs to keratinocytes in vitro was primarily mediated by alpha(E)beta(7) integrin, and blocking of the binding of alpha(E)beta(7) integrin to E-cadherin inhibited the lysis of keratinocytes by DETCs. Stable binding of E-cadherin on DETCs to plate-bound recombinant E-cadherin was observed only after 24-h culture in vitro. Cytokine production and degranulation by DETCs in response to suboptimal TCR cross-linking and mitogen stimulation were augmented by coligation of alpha(E)beta(7) integrin. In contrast, engagement of E-cadherin on DETCs with immobilized anti-E-cadherin Ab, plate-bound recombinant E-cadherin, and E-cadherin on keratinocytes inhibited DETC activation. Therefore, E-cadherin acts as an inhibitory receptor on DETCs, whereas alpha(E)beta(7) integrin acts as a costimulatory receptor. Differential expression of E-cadherin and alpha(E)beta(7) integrin on resting and activated DETCs, as well as their opposite functions in DETC activation, suggests that E-cadherin and alpha(E)beta(7) integrin on DETCs regulate their activation threshold through binding to E-cadherin on keratinocytes. The Journal of Immunology, 2011, 186: 6945-6954.