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Structural Factors Contributing to DM Susceptibility of MHC Class II/Peptide Complexes¹

Michael P. Belmares^*, Robert Busch, Kai W. Wucherpfennig^,, Harden M. McConnell^* and Elizabeth D. Mellins^2,

^* Department of Chemistry, Stanford University, and Department of Pediatrics, Stanford University Medical School, Stanford, CA 94305; and Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, and Department of Neurology, Harvard Medical School, Boston, MA 02115

Peptide loading of MHC class II (MHCII) molecules is assisted by HLA-DM, which releases invariant chain peptides from newly synthesized MHCII and edits the peptide repertoire. Determinants of susceptibility of peptide/MHCII complexes to DM remain controversial, however. Here we have measured peptide dissociation in the presence and the absence of DM for 36 different complexes of varying intrinsic stability. We found large variations in DM susceptibility for different complexes using either soluble or full-length HLA-DM. The DM effect was significantly less for unstable complexes than for stable ones, although this correlation was modest. Peptide sequence- and allele-dependent interactions along the entire length of the Ag binding groove influenced DM susceptibility. We also observed differences in DM susceptibility during peptide association. Thus, the peptide repertoire displayed to CD4⁺ T cells is the result of a mechanistically complicated editing process and cannot be simply predicted from the intrinsic stability of the complexes in the absence of DM.

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