Peptide presentation by major histocompatibility complex proteins (MHC) on antigen presenting cells is central to adaptive immune responses; thus, detailed characterization of molecular structure-function relationships determining MHC-peptide binding specificity and affinity is critical to understanding a variety of issues in immunity. Here, we demonstrate a robust approach for quantifying relative MHC-peptide binding affinities using yeast surface display and flow cytometry; using this method, we have examined specificity determinants at the P1 major anchor position of a model peptide binding to class II MHC HLA-DR1. We have also applied this method to screen a designed combinatorial library of HLA-DR1 mutants to identify novel sequences demonstrating altered peptide binding specificity with respect to the P1 anchor position. These results provide a basis for furthering the understanding of peptide-binding specificity and suggest the potential for engineering antigen presentation to provide molecular-level control of T cell responses.

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