Cluster of differentiation 96 (CD96) receptor (CD96)

CD96 is a type I transmembrane, heavily N-glycosylated immunoglobulin superfamily receptor expressed mainly on T cells and NK cells, functioning in immune adhesion and regulation within the CD155 (PVR) axis. Its primary ligand is CD155; CD96 competes with CD226 (DNAM-1) for CD155 binding, and structural studies show that the first Ig-like domain of CD96 mediates a conserved “lock-and-key” interaction with CD155. Alternative splicing produces distinct human isoforms; human and mouse CD96 differ in ligand specificity and potentially in signaling outcomes. CD96 is under investigation as an immune checkpoint target in cancer, with expression linked to tumor contexts such as glioma and to leukemia stem cells in AML. It has an ectodomain with three Ig-like domains: D1 (V-like) binds CD155; D2 can vary in human due to alternative splicing; D3 is C-like. It also has a single-pass transmembrane segment and cytoplasmic tail with signaling motifs; overall classified as an IgSF receptor and CD marker. The human CD96–CD155 complex structure (PDB 6ARQ) confirms D1-mediated binding and an ancillary key motif specifying ligand recognition. Its primary ligand is CD155 (also called PVR, necl-5). It competes within the CD155 axis with CD226 (DNAM-1) and TIGIT, forming a regulatory network controlling cytotoxic lymphocytes. Mouse CD96 can additionally bind nectin-1; this does not occur with human CD96.

Other names

T cell activation, increased late expression (TACTILE)CD96 moleculeCluster of Differentiation 96

Immune checkpoint inhibition via antibody blockade of CD96–CD155 (PVR) interaction to relieve inhibitory signaling on NK/T cells and enhance anti-tumor immunity. Potential modulation of the CD155/DNAM-1 (CD226)/TIGIT axis by altering ligand competition at CD155.