Natural killer group 2 member D ligands and DNAX accessory molecule 1 ligands (NKG2DLs and DNAM-1Ls)

Natural killer group 2 member D (NKG2D) ligands and DNAX accessory molecule 1 (DNAM-1) ligands are a collection of stress-induced cell surface proteins that serve as critical recognition signals for the innate and adaptive immune systems (PMID: 29463950). In humans, NKG2D ligands include MICA, MICB, and the ULBP family (ULBP1-6), while DNAM-1 ligands include CD155 (PVR) and CD112 (Nectin-2) (PMID: 31110339). These ligands are typically absent or expressed at low levels on healthy cells but are significantly upregulated on tumor cells in response to DNA damage, oncogenic transformation, or viral infection (PMID: 28615449). When these ligands bind to their respective activating receptors on natural killer (NK) cells and CD8+ T cells, they trigger potent cytotoxic activity and cytokine production to eliminate the aberrant cells (PMID: 12620224). However, tumors frequently employ evasion strategies such as proteolytic shedding of these ligands to create soluble decoys or upregulating inhibitory receptors like TIGIT to outcompete activating signals (PMID: 12193639, PMID: 19946306). Therapeutic interventions targeting this axis include NKG2D-based CAR-T cells, antibodies designed to prevent ligand shedding, and bispecific molecules that engage these ligands to redirect immune effector cells against the tumor (PMID: 29593067).

Other names

Stress-induced ligandsMICA/BULBPsPVRCD155Nectin-2CD112MIC ligandsUL16-binding proteins

Activation of NKG2D and DNAM-1 (CD226) receptors on NK cells and cytotoxic T cells to promote tumor cell lysis and cytokine production (PMID: 28615449).