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. 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, and the interaction of MHC and CD4/CD8 molecules, have been considered to occur independently 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 CD8alpha alpha homo- or CD8alpha beta heterodimers. Moreover, 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 interaction. CD8 should therefore be considered as an active participant in the T-cell recognition complex, rather than simply as an accessory molecule.

Redirecting human CD4+ T lymphocytes to the MHC class I-restricted melanoma antigen MAGE-A1 by TCR αβ gene transfer requires CD8α

“…In the case of CD8 + T lymphocytes, the CD8 molecule participates in the activation of these T lymphocytes by binding to the same peptide-MHC complex as does the TCR. 22,23 The role of CD8 may be two-fold: (A) stabilizing the interaction between TCR and peptide-MHC complex and enhancement of the T-cell activation by increasing the t 1/2 of the TCR/CD8/peptide-MHC complex; 24 (B) recruitment of CD8/p56lck to the TCR/CD3/z complex, which is essential for early signaling events in the T lympohocytes. 25,26 We demonstrated that CD4 + /CD8a + /tcTCR/z POS T lymphocytes specifically respond to immobilized HLA-A1/MAGE-A1 complexes and HLA-A1 + /MAGE-A1 + melanoma cells, that is, they produce IFN-g, TNFa and IL-2.…”

CD8-Independent Tumor Cell Recognition Is a Property of the T Cell Receptor and Not the T Cell

“…Generally, TCRs bind to the peptide/MHC complexes with lower affinity than Ab/Ag interactions (5)(6)(7). One function of CD4 and CD8 is to enhance the overall affinity of the complex through binding to the ␤ 2 domain of MHC class II molecules and the ␣ 3 domain of MHC class I molecules, respectively (8,9). CD4 and CD8 also provide signal transduction by association of their cytoplasmic domains with the tyrosine kinase Lck (10).…”

Soluble CD8 Attenuates Cytotoxic T Cell Responses Against Replication-Defective Adenovirus Affording Transprotection of Transgenes In Vivo

“…In addition, the ␣-chain of the CD8 coreceptor binds to the ␣3 domain of MHC-I (28 -32) with very low affinity (ϳ200 M in solution (33)). The precise way in which CD8 facilitates T cell activation is unclear, but it includes stabilization of the T cell-target contact and activation of lck (10,12,34,35). One model suggests that the TCR first engages the peptide MHC complex; this leads to lck activation and subsequent recruitment of CD8 into the multimolecular TCR/ CD3/MHC-I complex (33,36).…”