Natural killer group 2D ligands (MHC class I polypeptide-related sequence A, MHC class I polypeptide-related sequence B, and UL16-binding proteins 1-6) (NKG2DLs)

NKG2D ligands (NKG2DLs), which include MHC class I polypeptide-related sequence A (MICA), MHC class I polypeptide-related sequence B (MICB), and the UL16-binding protein family (ULBP1-6), are stress-induced proteins that are typically absent from healthy tissues but highly expressed on the surface of transformed or infected cells (UniProt Q29983, Q29980). These ligands act as critical danger signals recognized by the activating receptor NKG2D, which is found on natural killer (NK) cells, CD8+ T cells, and γδ T cells (PMID: 30918153). Upon binding, they trigger potent immune responses, including direct cell-mediated cytotoxicity and the production of pro-inflammatory cytokines, to eliminate the target cells (Frontiers in Immunology, 2019). However, many tumors develop evasion mechanisms by proteolytically shedding these ligands from their surface using metalloproteinases like ADAM10 and ADAM17 (PMID: 29593067). This shedding results in soluble forms (sMICA/B) that act as decoys, systemically inhibiting NK cell activity and causing the internalization of the NKG2D receptor (Nature, 2018). Therapeutic approaches currently under investigation include monoclonal antibodies designed to prevent ligand shedding (e.g., 7C6), NKG2D-based chimeric antigen receptor (CAR) T-cell therapies (e.g., CYAD-01), and epigenetic modulators like HDAC inhibitors that upregulate ligand expression to restore immune recognition (Celyad Oncology; NIH).

Other names

MICAMICBULBP1ULBP2ULBP3ULBP4ULBP5ULBP6RAET1 proteinsStress-induced ligandsNKG2D ligandsMHC class I-related chain AMHC class I-related chain BUL16-binding proteins

Activation of NKG2D-mediated cytotoxicity, prevention of ligand shedding (stabilization), induction of ligand expression via HDAC inhibition, and CAR-T cell-mediated tumor lysis.