A binding site for the T-cell co-receptor CD8 on the α3 domain of HLA-A2

Adhesion measurements between CD8 and 48 point mutants of HLA-A2.1 show that the CD8 α-chain binds to the α 3 domain of HLA-A2.1. Three clusters of α 3 residues contribute to the binding, with an exposed, negatively charged loop (residues 223–229) playing a dominant role. CD8 binding correlates with cytotoxic T-cell recognition and sensitivity to inhibition by anti-CD8 antibodies. Impaired alloreactive T-cell recognition of an HLA-A2.1 mutant with reduced affinity for CD8 is not restored by functional CD8 binding sites on an antigenically irrelevant class I molecule. Therefore, complexes of CD8 and the T-cell receptor bound to the same class I major histocompatibility complex molecule seem to be necessary for T-cell activation.