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Decreased Binding of Peptides-MHC Class I (pMHC) Multimeric Complexes to CD8 Affects Their Binding Avidity for the TCR But Does Not Significantly Impact on pMHC/TCR Dissociation Rate¹

Valérie Dutoit^2,*,, Philippe Guillaume^2,, Maha Ayyoub^*,, Charles S. Hesdorffer, Immanuel F. Luescher and Danila Valmori^3,*,

^* Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, University Hospital (Centre Hospitalier Universitaire Vaudois), Lausanne, Switzerland; Ludwig Institute Clinical Trial Center, Division of Medical Oncology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032; and Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Lausanne, Switzerland

The CD8 coreceptor plays a crucial role in both T cell development in the thymus and in the activation of mature T cells in response to Ag-specific stimulation. In this study we used soluble peptides-MHC class I (pMHC) multimeric complexes bearing mutations in the CD8 binding site that impair their binding to the MHC, together with altered peptide ligands, to assess the impact of CD8 on pMHC binding to the TCR. Our data support a model in which CD8 promotes the binding of TCR to pMHC. However, once the pMHC/TCR complex is formed, the TCR dominates the pMHC/TCR dissociation rates. As a consequence of these molecular interactions, under physiologic conditions CD8 plays a key role in complex formation, resulting in the enhancement of CD8 T cell functions whose specificity, however, is determined by the TCR.

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