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

Abstract

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 γδ T cells, known as dendritic epidermal T cells (DETCs), but they express another receptor for E-cadherin, αE(CD103)β7 integrin, as well. In this study, we analyzed functional differences between E-cadherin–mediated homophilic binding and heterophilic binding of αEβ7 integrin to E-cadherin in heterotypic intercellular adhesion of DETCs to keratinocytes. E-cadherin, but not αEβ7 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 αEβ7 integrin, and blocking of the binding of αEβ7 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 αEβ7 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 αEβ7 integrin acts as a costimulatory receptor. Differential expression of E-cadherin and αEβ7 integrin on resting and activated DETCs, as well as their opposite functions in DETC activation, suggests that E-cadherin and αEβ7 integrin on DETCs regulate their activation threshold through binding to E-cadherin on keratinocytes.

E-cadherin promotes accumulation of a unique memory CD8 T-cell population in murine salivary glands

“…On the contrary, expression of E-cadherin on lymphocytes has been analyzed in only a few studies. E-cadherin has been found on fetal thymocytes, IEL, and dendritic epidermal T cells (DETC) in the skin (21)(22)(23), and it has also recently been postulated to function as an inhibitory receptor on DETC (24). Interestingly, leukocytes infiltrating SMG of autoimmunityprone NOD mice have further been reported to express E-cadherin (20).…”

“…E-cadherin is a well-known homotypic cell-cell adhesion molecule for epithelial cells, and heterotypic binding of E-cadherin on epithelial tissues to CD103 on lymphocytes is well documented (17-19). In contrast, the functional role of E-cadherin on the surface of lymphocytes has not yet been addressed in vivo (20)(21)(22)(23)(24).Examining the tissue distribution of virus-specific memory CD8 T cells after systemic lymphocytic choriomeningitis virus (LCMV) infection, we detected an enrichment of LCMV-specific memory T cells in SMG that resembled T RM cells. In the present report, we characterize the unique phenotype and the functional features of these T cells.…”

“…E-cadherin is a well-known homotypic cell-cell adhesion molecule for epithelial cells, and heterotypic binding of E-cadherin on epithelial tissues to CD103 on lymphocytes is well documented (17)(18)(19). In contrast, the functional role of E-cadherin on the surface of lymphocytes has not yet been addressed in vivo (20)(21)(22)(23)(24).…”

Regulation and function of the E-cadherin/catenin complex in cells of the monocyte-macrophage lineage and DCs

“…22 The in vivo relevance of these findings is illustrated by CD103-deficient mice, which have reduced numbers of resident IELs and DETCs, 23 probably because of a combination of mechanisms: (1) diminished retention in epithelia; (2) an altered motility 24 ; and (3) a lack of ␣ E (CD103)␤ 7 -mediated costimulation. 25 Along the same line, retention of regulatory T cells in cutaneous wounds is mediated by CD103, 26 and TGF-␤-mediated expression of CD103 on CD8 ϩ T cells promotes their cytotoxic activity against E-cadherin ϩ targets. 27,28 Finally, CD103 expression distinguishes subpopulations of DCs that are found in lymphoid and various nonlymphoid organs and that display distinctive functions, such as cross-presentation of antigens in the draining lymph nodes (LNs), instruction of tissue-homing capacities on the activated T cells, and induction of regulatory T cells.…”

γδ-T cells: an unpolished sword in human anti-infection immunity

“…It has been found that the expression of junctional adhesion molecule-like protein 68 and high-mobility group box 1 69 by cd-T cells provides positive signals for the activation of cd-T cells, whereas stimulation with E-cadherin downregulates their functions. 70 The natural killer (NK) cell receptor family is another important group of costimulators for regulating the activity of cd-T cells, and the balance among stimulatory and inhibitory natural killer WW (NK) cell receptor signals might determine the functions of cd-T cells. For example, NKG2D and NKG2C promote the activation of cd-T cells, whereas NKG2A transfers inhibitory signals to them.…”