INVARIANT CHAIN ASSOCIATION WITH HLA-DR MOLECULES INHIBITS IMMUNOGENIC PEPTIDE BINDING

CLASS II major histocompatibility complex (MHC) molecules are heterodimeric cell surface glycoproteins which bind and present immunogenic peptides to T lymphocytes. Such peptides are normally derived from protein antigens internalized and proteolytically degraded by the antigen-presenting cell1. Class I MHC molecules also bind immunogenic peptides, but these are derived from proteins synthesized within the target cell2. Whereas class I molecules seem to bind peptides in the endoplasmic reticulum3-5, class II molecules are thought to bind peptides late in transport. Intracellular class II molecules associate in the endoplasmic reticulum with a third glycoprotein, the invariant (I) chain, which is proteolytically removed before cell surface expression of the αβ class II heterodimer6,7. It has been suggested that the I chain prevents peptides from associating with class II molecules early in transport8. Preventing such binding until the class II molecules enter an endosomal compartment could maintain the functional dichotomy between class I and class II MHC molecules. We have examined the ability of I chain-associated HLA-DR5 moleculesto bind a well characterized influenza haemagglutinin-derived peptide (HAp). The results show that whereas mature HLA-DR αβ dimers effectively bind this peptide, the I chain-associated form does not. © 1990 Nature Publishing Group.