MAJOR HISTOCOMPATIBILITY COMPLEX CLASS II-RESTRICTED PRESENTATION OF SECRETED AND ENDOPLASMIC-RETICULUM RESIDENT ANTIGENS REQUIRES THE INVARIANT CHAINS AND IS SENSITIVE TO LYSOSOMOTROPIC AGENTS

We have tested the involvement of the invariant chains (Ii) p31 and p4 1 in the presentation of peptides derived from hen egg lysozyme (HEL) constructs targeted to different intracellular compartments within tra nsfected fibroblasts. The endogenous HEL constructs were either presen t in the cytosol (HELc), secreted (HELs), or linked to the mammalian ( KDEL C-terminal sequence that causes retention of HEL in the endoplasm ic reticulum (ER)/pre-Golgi recycling compartment (HELr). Using Ii-neg ative antigen-presenting cells, the presentation of HELr to a HEL 46-6 1 specific T cell hybridoma was far less efficient than the presentati on of the HELs. High levels of Ii expression enhanced drastically the presentation of the HEL 46-61 determinant derived from both HELr and H ELs. HELr and HELs presentation was fully sensitive to lysosomotropic agents such as chloroquine, indicating that the formation of complexes between major histocompatibility complex (MHC) class II molecules and determinants derived from endogenous antigens entering the secretory pathway is taking place in an acidic compartment. The degradation and dissociation of Ii might be a prerequisite for the efficient presentat ion of endogenously derived determinants by MHC class II molecules, as for the presentation of most exogenous antigens. All our results are compatible with the notion that endogenous molecules being translocate d into the lumen of the ER could be presented by class II molecules th rough a processing pathway involving an acidic compartment in which Ii chains dissociate from class II molecules.