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From the Howard Hughes Medical Institute, Yale University School of Medicine, Section of
Immunobiology, New Haven, Connecticut 06510
Major histocompatibility complex (MHC) class II-positive cell lines which lack HLA-DM expression accumulate class II molecules associated with residual invariant (I) chain fragments
(class II-associated invariant chain peptides [CLIP]). In vitro, HLA-DM catalyzes CLIP dissociation from class II-CLIP complexes, promoting binding of antigenic peptides. Here the physical interaction of HLA-DM with HLA-DR molecules was investigated. HLA-DM complexes with class II molecules were detectable transiently in cells, peaking at the time when the class II
molecules entered the MHC class II compartment. HLA-DR 
dimers newly released from I
chain, and those associated with I chain fragments, were found to associate with HLA-DM in
vivo. Mature, peptide-loaded DR molecules also associated at a low level. These same species,
but not DR-I chain complexes, were also shown to bind to purified HLA-DM molecules in
vitro. HLA-DM interaction was quantitatively superior with DR molecules isolated in association with CLIP. DM-DR complexes generated by incubating HLA-DM with purified DR
CLIP contained virtually no associated CLIP, suggesting that this superior interaction reflects a prolonged HLA-DM association with empty class II dimers after CLIP dissociation. Incubation of peptide-free dimers in the presence of HLA-DM was found to prolong their
ability to bind subsequently added antigenic peptides. Stabilization of empty class II molecules
may be an important property of HLA-DM in facilitating antigen processing.
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