The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/2000/1/335/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 2, January 17, 2000 335-346


Original Article

Critical Role for CD8 in T Cell Receptor Binding and Activation by Peptide/Major Histocompatibility Complex Multimers

Mark A. Danielsa and Stephen C. Jamesona
a Center for Immunology, Department of Lab Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota 55455

Recent data using MHC/peptide tetramers and dimers suggests that the T cell coreceptors, CD4 and CD8, although important for T cell activation, do not play a direct role in facilitating T cell receptor (TCR) binding to multivalent MHC/peptide ligands. Instead, a current model proposes that coreceptors are recruited only after a stable TCR–MHC/peptide complex has already formed and signaled. In contrast, we show using multimeric class I MHC/peptide ligands that CD8 plays a critical (in some cases obligatory) role in antigen-specific TCR binding. T cell activation, measured by calcium mobilization, was induced by multimeric but not monomeric ligands and also showed CD8 dependency. Our analysis using anti-CD8 antibodies revealed that binding to different epitopes of CD8 can either block or augment TCR–MHC/peptide interaction. These effects on TCR binding to high-affinity agonist ligands were even more pronounced when binding to multimeric low-affinity ligands, including TCR antagonists, was studied. Our data have important implications for the role of CD8 in TCR binding to MHC/peptide ligands and in T cell activation. In addition, our results argue against the view that multimeric MHC/peptide ligands bind directly and solely to the TCR; rather, our data highlight a pivotal contribution of CD8 for this association.

Key Words: MHC/peptide tetramers, T cell activation, cytotoxic T lymphocyte, calcium, flow cytometry


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