CD8 enhances formation of stable T-cell receptor/MHC class I molecule complexes

Abstract

T-CELL antigen receptors (TCR) generally interact with moderate affinity with the complex formed by major histocompatibility complex (MHC) molecules and foreign peptides^1–7. MHC/TCR recognition is followed by the generation of a signal to the T cell through a monomorphic multicomponent system that includes the CD3 complex and accessory molecules such as CD4 and CD8. The interaction between the extracellular domains of MHC and TCR molecules^1–7, and the interaction of MHC and CD4/CD8 molecules^8–10, have been considered to occur indepen-dently of one another. We report here that the affinity of CD8 dimers for MHC class I molecules is independent of haplotype and peptide content, and that the affinity of the TCR for its specific ligand is enhanced through a reduced 'off" rate in the presence of either CD8αα homo- or CD8αβ heterodimers. More-over, CD8 seems to help recognition of the specific MHC–peptide complex either by guiding an energetically favourable docking of TCR onto MHC, or by inducing conformational changes in the MHC complex that can augment the TCR/MHC–peptide inter-action. CD8 should therefore be considered as an active partici-pant in the T-cell recognition complex, rather than simply as an accessory molecule.