The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1996/12/2153/ $5.00
The Journal of Experimental Medicine, Volume 184, Number 6, December 1, 1996 2153-2166

Articles

HLA-DM Interactions with Intermediates in HLA-DR Maturation and a Role for HLA-DM in Stabilizing Empty HLA-DR Molecules

Lisa K. Denzin, Craig Hammond, and Peter Cresswell

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 {alpha}β 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 {alpha}βCLIP 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 {alpha}β 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.

Address correspondence to Peter Cresswell, Howard Hughes Medical Institute, Yale University School of Medicine, Section of Immunobiology, 310 Cedar Street, 415 FMB, New Haven, CT 06510.

This work was supported by National Institutes of Health grant AI 23081, a gift from Pfizer Inc., and the Howard Hughes Medical Research Institute. L.K. Denzin is supported by a fellowship from the Patrick and Catherine Weldon Donaghue Medical Research Foundation.

1 Abbreviations used in this paper: B-LCL, B-lymphoblastoid; CIIV, class II– containing vesicles; CLIP, class II–associated invariant chain peptides; DOC, deoxycholate; MIIC, MHC class II compartment.


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