NKG2D acts as an activating and a co-stimulatory receptor. NKG2D is a type-2 transmembrane homodimer that signals via association with adapter molecules DAP10 or DAP12. Association with DAP12 leads to phosphorylation of the ITAM and triggering of the Syk and/or Zap70 signaling cascade. Association with DAP10 results in tyrosine phosphorylation on the YINM motif and recruitment of the PI3K and Grb2 cascade. On NK cells, NKG2D serves as an activation receptor, such that NKG2D engagement is sufficient to trigger NK cell-mediated cytotoxicity and cytokine production. In contrast, NKG2D acts as a co-stimulatory receptor on CD8 T cells, requiring TCR-mediated signaling for their full activation. Grb2, growth factor receptor-bound protein 2; IFN-γ, interferon γ; ITAM, immunoreceptor tyrosine-based activating motif; PI3K, phosphoinositide 3-kinase; Syk, spleen tyrosine kinase; TCR, T cell receptor; TNF-α, tumor necrosis factor α; Zap70, zeta-chain associated protein kinase 70.