The cell surface glycoprotein CD8 functions as a coreceptor with the TCR on cytotoxic T lymphocytes. Mutational analysis of the binding site of CD8 for MHC class I predicted that distinct surfaces of CD8 would interact with both the α2 and α3 domains of class I. Using a cell-cell adhesion assay, we identified three residues Q115, D122, and E128 in the α2 domain of class I critical for interaction with CD8. The side chains of these residues point towards a cavity formed by the α1/α2 platform, the α3 domain and β- microglobulin (β2m) of class I. These residues were predicted to contact CD8 based on a bivalent model of interaction between one CD8α/α homodimer and two MHC class I molecules. These results therefore provide support for the model.
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