Natural cytotoxicity receptors, NKG2D, and DNAM-1 (NKG2D, DNAM-1)

NKG2D and DNAM-1 are major activating receptors primarily expressed on natural killer (NK) cells and subsets of T cells. They play crucial roles in innate immune surveillance, recognizing stress-induced ligands on the surface of transformed, infected, or damaged cells and triggering cytotoxic responses. NKG2D (encoded by KLRK1) is a C-type lectin-like receptor that requires the adaptor protein DAP10 for signal transduction and binds ligands such as MICA, MICB, and ULBPs. DNAM-1 (CD226) is an immunoglobulin superfamily receptor that interacts mainly with CD155 (PVR) and CD112 (Nectin-2), cooperating with other NK/T cell receptors and modulated by inhibitory molecules such as TIGIT. Both play prominent roles in anti-tumor immunity, infectious disease resistance, and can be dysregulated in autoimmune and inflammatory conditions. Their ligand expression is frequently induced in response to cellular stress, DNA damage, infection, or malignancy, making them important checkpoints in therapeutic immunomodulation.

Other names

NKG2D: Natural killer group 2, member DNKG2D: KLRK1NKG2D: killer cell lectin-like receptor subfamily K, member 1DNAM-1: CD226DNAM-1: DNAX accessory molecule-1Natural cytotoxicity receptors (NCRs): NKp30 (NCR3)Natural cytotoxicity receptors (NCRs): NKp44 (NCR2)Natural cytotoxicity receptors (NCRs): NKp46 (NCR1)

Enhancement of NK- and CD8+ T cell–mediated killing (agonist approaches); Blocking ligand–receptor interaction to prevent tissue damage or autoimmunity (antagonist approaches); Indirect pharmacodynamic modulation through cytokine upregulation or immune checkpoint blockade