Killer cell lectin-like receptor subfamily K member 1 (NKG2D) on cytokine-induced memory-like natural killer cells (NKG2D)

NKG2D (Natural Killer Group 2 Member D), encoded by the KLRK1 gene, is a primary activating receptor expressed on natural killer (NK) cells and certain T cell subsets (UniProt P26718). Cytokine-induced memory-like (CIML) NK cells represent a specialized therapeutic population generated by ex vivo activation with IL-12, IL-15, and IL-18, which results in enhanced effector function and prolonged persistence compared to conventional NK cells (Romee et al., Sci Transl Med, 2016). The NKG2D receptor on these cells recognizes stress-induced ligands, including MICA, MICB, and the ULBP family, which are typically absent on healthy cells but upregulated in malignant or infected cells (PubMed: 11777960). Upon ligand engagement, NKG2D signals through the DAP10 adapter molecule to trigger the release of cytotoxic granules (perforin and granzymes) and pro-inflammatory cytokines like IFN-gamma. This interaction is a critical axis in cancer immunotherapy, particularly for treating acute myeloid leukemia (AML) and solid tumors using adoptive cell transfers like WU-NK-101 or NKG2D-targeted chimeric antigen receptor (CAR) therapies (Wugen, 2024). However, therapeutic efficacy can be challenged by tumor-mediated shedding of soluble ligands (sMICA), which acts as a decoy to downregulate NKG2D expression and facilitate immune evasion (PubMed: 12114504).

Other names

KLRK1CD314Natural killer group 2 member DCIML-NK cellsNKG2-D type II integral membrane protein

Activation of NK cell-mediated cytotoxicity and cytokine release through the engagement of NKG2D with stress-induced ligands (MICA, MICB, ULBPs) on tumor cells, signaling via the DAP10 adapter protein.