CD8 co-receptor binding to the α3 domain of HLA class I (CD8-HLA-I interaction)

The CD8 co-receptor binding to the α3 domain of HLA class I is a fundamental protein-protein interaction (PPI) that governs the activation and sensitivity of cytotoxic T lymphocytes (CTLs) (Wooldridge et al., J Immunol 2003). CD8, a transmembrane glycoprotein, binds to the invariant α3 domain of the Major Histocompatibility Complex (MHC) class I molecule, which is spatially distinct from the peptide-binding groove recognized by the T-cell receptor (TCR) (Salter et al., Nature 1990). This binding stabilizes the TCR-peptide-MHC (pMHC) complex and facilitates the recruitment of the intracellular kinase Lck to the TCR-CD3 complex, amplifying signaling and lowering the threshold for T-cell activation (Hutchinson et al., J Biol Chem 2003). In oncology, this interaction is a target for enhancement to improve the efficacy of cancer immunosurveillance and adoptive T-cell therapies (Bridgeman et al., Clin Med Journals 2012). Conversely, in autoimmune diseases and organ transplantation, blocking this interaction can suppress unwanted T-cell responses (Connolly et al., PNAS 1990). Therapeutic agents under investigation include monoclonal antibodies, engineered high-affinity MHC variants, and synthetic peptides that modulate the affinity of the CD8-HLA-I interface (Frontiers in Immunology, 2024).

Other names

CD8-MHC class I interactionCD8-α3 domain bindingCD8-HLA-A/B/C interactionCD8-MHC-I complexCD8-pMHC-I interaction

Modulation of T-cell receptor (TCR) sensitivity and activation threshold by either enhancing (agonism) or blocking (antagonism) the recruitment of Lck to the TCR-CD3 complex through the CD8-HLA-I α3 domain interface (Wooldridge et al., J Immunol 2003).