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Cutting Edge: TCR Contacts as Anchors: Effects on Affinity and HLA-DM Stability ¹

Blood Research Institute, Blood Center of Southeastern Wisconsin, Milwaukee, WI 53201; and Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53201

Peptides presented via the class II MHC (MHCII) pathway are selected based on affinity for MHCII and stability in the presence of HLA-DM. Currently, epitope selection is thought to be controlled by the ability of peptide to sequester "anchor" residues into pockets in the MHCII. Residues exhibiting higher levels of solvent accessibility have been shown to contact TCR, but their roles in affinity and complex stability have not been directly studied. Using the HLA-DR1-binding influenza peptide, hemagglutinin (306–318), as a model, we show that side chain substitutions at these positions influence affinity and HLA-DM stability. Multiple substitutions reduce affinity to a greater extent than the loss of the major P1 anchor residue. We propose that these effects may be mediated through the H-bond network. These results demonstrate the importance of solvent-exposed residues in epitope selection and blur the distinctions between anchor and TCR contact residues.

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