ITAM-containing adaptors regulate NKG2D-mediated cytotoxicity in human NK cells (138.15)

NKG2D is expressed on cytotoxic lymphocytes and is an important immunosurveillance receptor that recognizes stress ligands such as MICA on tumor cells or virally infected cells. Unlike traditional immune activating receptors, NKG2D couples to the non-ITAM-containing transmembrane adaptor DAP10, which recruits PI3K and Grb2 to initiate target cell lysis. Current understanding predicts an ITAM-independent mechanism of NKG2D-mediated cytotoxicity. However, we show that in primary human NK cells, the ITAM-containing adaptors DAP12, FcϵR1γ, and CD3ζ selectively regulate the Grb2-Vav1 branch of NKG2D-mediated signal transduction and cytotoxicity. Furthermore, this ITAM-adaptor regulation of NKG2D is independent of ITAM activation. Thus our data reveal a more complex interplay between NKG2D and other activating receptors than was previously imagined, and we have uncovered a novel mechanism of ITAM-adaptor regulation of cell-mediated cytotoxicity. A more thorough understanding of immunoreceptor signaling networks will lead to more precise therapies when fighting diseases such as cancer, autoimmunity, and infection.