THE BIOGENESIS OF THE MHC CLASS-II COMPARTMENT IN HUMAN I-CELL DISEASE B-LYMPHOBLASTS

The localization and intracellular transport of major histocompatibili ty complex (MHC) class II molecules and lysosomal hydrolases were stud ied in I-Cell Disease (ICD) B lymphoblasts, which possess a mannose 6- phosphate (Man-6-P)-independent targeting pathway for lysosomal enzyme s. In the trans-Golgi network (TGN), MHC class II-invariant chain comp lexes colocalized with the lysosomal hydrolase cathepsin D in buds and vesicles that lacked markers of clathrin-coated vesicle-mediated tran sport. These vesicles fused with the endocytic pathway leading to the formation of ''early'' MHC class II-rich compartments (MIICs). Similar structures were observed in the TGN of normal beta lymphoblasts altho ugh they were less abundant. Metabolic labeling and subcellular fracti onation experiments indicated that newly synthesized cathepsin D and M HC class II-invariant chain complexes enter a non-clathrin-coated vesi cular structure after their passage through the TGN and segregation fr om the secretory pathway. These vesicles were also devoid of the catio n-dependent mannose 6-phosphate (Man-6-P) receptor, a marker of early and late endosomes, These findings suggest that in ICD B lymphoblasts the majority of MHC class II molecules are transported directly from t he TGN to ''early'' MIICs and that acid hydrolases can be incorporated into MIICs si multaneously by a Man-6-P-independent process.