STABLE SURFACE EXPRESSION OF INVARIANT CHAIN PREVENTS PEPTIDE PRESENTATION BY HLA-DR

Class II major histocompatibility complex (MHC) molecules are cell surface glycoproteins that bind and present immunogenic peptides to T cells. Intracellularly, class II molecules associate with a polypeptide referred to as the invariant (Ii) chain. Ii is proteolytically degraded and dissociates from the class II complex prior to cell surface expression of the mature class II alpha-beta-heterodimer. Using human fibroblasts transfected with HLA-DR1 and Ii cDNAs, we now demonstrate that truncation of the cytoplasmic domain of Ii results in the failure of Ii to dissociate from the alpha-beta-Ii complex and leads to stable expression of class II alpha-beta-Ii complexes on the cell surface. Furthermore, biochemical analysis and peptide presentation assays demonstrated that transfectants with stable surface alpha-beta-Ii complexes expressed very few free alpha-beta heterodimers at the surface and were very inefficient in their ability to present immunogenic peptides to T cells. These results support the hypothesis that the cytoplasmic domain of Ii is responsible for endosomal targeting of alpha-beta-Ii and directly demonstrate that association with Ii interferes with the antigen presentation function of class II molecules.