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Characterization of the Interactions Between MHC Class I Subunits: A Systematic Approach for the Engineering of Higher Affinity Variants of ß₂-Microglobulin¹

Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

Human ß₂m (hß₂m) binds to murine MHC I molecules with higher affinity than does murine ß₂m and therefore can be used as a model system to define and dissect the interactions between ß₂m and MHC I heavy chains that promote the stability of the complex. In the present study we compare three-dimensional crystal structures of human and murine MHC I molecules and use functional studies of chimeric human:murine ß₂m variants to define a region of ß₂m that is involved in the higher affinity of hß₂m for murine MHC I heavy chains. Further examination of the three-dimensional structure in this region revealed conformational differences between human and murine ß₂m that affect the ability of an aspartic acid residue at position 53 (D53) conserved in both ß₂ms to form an ionic bond with arginine residues at positions 35 and 48 of the heavy chain. Mutation of residue D53 to either asparagine (D53N) or valine (D53V) largely abrogated the stabilizing effects of hß₂m on murine MHC I expression in a predictable manner. Based on this observation a variant of hß₂m was engineered to create an ionic bond between the heavy chain and ß₂m. This variant stabilizes cell surface H-2D^d heavy chains to a greater extent than wild-type hß₂m. Studying these interactions in light of the growing database of MHC I crystal structures should allow the rational design of higher affinity hß₂m variants for use in novel peptide-based vaccines capable of inducing cell-mediated immune responses to viruses and tumors.

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