HOW MHC CLASS-II MOLECULES REACH THE ENDOCYTIC PATHWAY

We have examined trafficking of major histocompatibility complex (MHC) class II molecules in human B cells exposed to concanamycin B, a high ly specific inhibitor of the vacuolar H+-ATPases required for acidific ation of the vacuolar system and for early to late endosomal transport . Neutralization of vacuolar compartments prevents breakdown of the in variant chain (Ii) and blocks conversion of MHC class II molecules to peptide-loaded, SDS-stable alpha beta dimers. Ii remains associated wi th alpha beta and this complex accumulates internally, as ascertained biochemically and by morphological methods. In concanamycin B-treated cells, a slow increase (>20-fold) in surface expression of Ii, mostly complexed with alpha beta, is detected. This surface-disposed fraction of alpha beta Ii is nevertheless a minor population that reaches the cell surface directly, or is routed via early endosomes as intermediar y stations. In inhibitor-treated cells, the bulk of newly synthesized alpha beta Ii is no longer accessible to fluid phase endocytic markers . It is concluded that the majority of alpha beta Ii is targeted direc tly from the trans-Golgi network to the compartment for peptide loadin g, bypassing the cell surface and early endosomes en route to the endo cytic pathway.