NKG2D ligation without T cell receptor engagement triggers both cytotoxicity and cytokine production in dendritic epidermal T cells

NKG2D is an activating receptor that recognizes self-ligands induced on stressed, infected, or transformed cells. In mice, two NKG2D isoforms (NKG2D-S (short) and NKG2D-L (long)) that associate differentially with DAP10 and DAP12 adaptor proteins exist. Differential expression of these isoforms and adaptor proteins depending on the activating state and cell types determines distinct functional outcomes of NKG2D ligation: direct activation of cytotoxicity in natural killer (NK) cells and cytokine production in activated NK cells, but only costimulation in activated CD8(+) T cells. Intraepithelial gamma delta T cells of the mouse skin, termed dendritic epidermal T cells (DETCs), were also shown to express NKG2D, but the NKG2D isoform(s) expressed in DETCs have not been determined. Furthermore, functional outcomes of NKG2D ligation in DETCs are largely unknown, although costimulation of DETC-mediated cytotoxicity by NKG2D was demonstrated. Here, we show that DETCs constitutively express NKG2D-S, NKG2D-L, DAP10, and DAP12 transcripts as well as cell surface NKG2D protein. Blocking of NKG2D inhibited DETC-mediated cytotoxicity against target cells that do not express T cell receptor ligands. Cross-linking of NKG2D on DETCs induced IFN-gamma production. These findings demonstrate that DETCs constitutively express NKG2D that acts as a primary activating receptor, and indicate its important role in cutaneous immune surveillance.