Introducing endogenous antigens into the major histocompatibility complex (MHC) class II presentation pathway. Both Ii mediated inhibition and enhancement of endogenous peptide/MHC class II presentation require the same Ii domains

The invariant chain (Ii) plays a key role in regulating the antigen present ation function of major histocompatibility complex (MHC) class II molecules . Ii also influences the presentation of usually excluded endogenously synt hesized proteins into the MHC class II presentation pathway. To evaluate th e role of Ii in the generation of peptide-MHC class II complexes derived fr om endogenously synthesized proteins, we tested mutant Ii constructs in two model systems. Go-expression of wild-type Ii inhibits the presentation of hen-egg lysozyme (HEL) 35-45/A(k) complex, but enhances the presentation of ovalbumin (OVA) 247-265/A(k) complex from endogenously synthesized I-ILL o r OVA precursors. The differential sensitivity of these antigens to chloroq uine was consistent with their being processed in distinct compartments. Ne vertheless, with a panel of Ii deletion constructs we show here that both t he Ii-mediated inhibition and enhancement functions require the endosomal t argeting and CLIP residues. Surprisingly, the Ii mutant lacking the endopla smic reticulum lumenal residues 126-215, despite apparently lower expressio n, was at least as effective as full-length Ii in antigen presentation assa ys. Thus, alternative pathways exist for processing endogenously expressed antigens, and Ii-mediated inhibition and enhancement of peptide/MHC class I I expression depend upon the same regions, with neither requiring the 89 C- terminal, lumenal Ii residues.