Critical role for CD8 in binding of MHC tetramers to TCR: CD8 antibodies block specific binding of human tumor-specific MHC-Peptide tetramers to TCR

There are conflicting opinions about the role that the T cell coreceptors C D4 and CD8 play in TCR binding and activation. Recent evidence from transge nic mouse models suggests that CD8 plays a critical role in TCR binding and activation by peptide-MHC complex multimers (tetramers). Here we show with a human CTL clone specific for a tumor-associated MHC-peptide complex that the binding of tetramers to the TCR on these cells is completely blocked b y anti-human CD8 Abs. Moreover, the staining of CTLs with specific MHC-pept ide tetramers simultaneously with anti-CD8 Abs was completely blocked with three different anti-CD8 Abs. This blockage was mediated by anti-CD8 Abs bu t not anti-CD3 Abs and was dose dependent. The blocking effect of the anti- CD8 Abs was attributable to directly inhibiting tetramer binding and was no t attributable to Ab-mediated TCR-CD8 internalization and down-regulation. Our results have important implications in TCR binding to MHC-peptide tetra mers. MHC-peptide tetramers are widely used today in combination with anti- CD8 Abs for the phenotypic analysis of T cell populations and in the study of T cell responses under various pathological conditions such as infectiou s diseases and cancer. Our results indicate that also in the human system C D8 plays a critical role in the interaction of MHC-peptide multimers with T CR.