Natural Killer cell activating ligands (NKALs)

Stressed or malignant cells with downregulated MHC class I and expression of NK-activating ligands describes a cellular phenotype that is a key target for Natural Killer (NK) cell-mediated immune surveillance. This state occurs when cells undergo pathological stress, such as oncogenic transformation or viral infection, resulting in the downregulation of Major Histocompatibility Complex (MHC) class I molecules—a strategy used to evade CD8+ T-cells—and the simultaneous upregulation of stress-induced ligands like MHC class I-related chain A (MICA), MHC class I-related chain B (MICB), and UL16-binding proteins (ULBPs) (Lanier, 2005). NK cells recognize this “missing-self” and “induced-self” profile through a balance of surface receptors; the absence of MHC-I prevents the triggering of inhibitory receptors (e.g., Killer-cell immunoglobulin-like receptors, NKG2A), while the presence of activating ligands triggers receptors like NKG2D (Diefenbach & Raulet, 2002). This shift in signaling leads to NK cell activation, degranulation, and the subsequent lysis of the target cell via perforin and granzymes. Therapeutic approaches targeting this axis include monoclonal antibodies that block inhibitory checkpoints (e.g., Monalizumab, Lirilumab), bispecific NK cell engagers (e.g., AFM13), and CAR-NK or CAR-T cells engineered to express NKG2D or other activating receptors (Shimasaki et al., 2020).

Other names

NKG2D ligandsStress-induced ligandsMICA/BULBPMissing-self targetsMHC class I-related chain A/B

Enhancement of Natural Killer (NK) cell-mediated cytotoxicity by blocking inhibitory receptors (e.g., Killer-cell immunoglobulin-like receptors, NKG2A) or directly activating NK cells via the recognition of stress-induced ligands (e.g., MHC class I-related chain A/B) on target cells (Lanier, 2005; Shimasaki et al., 2020).