INVARIANT CHAIN AND DM EDIT SELF-PEPTIDE PRESENTATION BY MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) CLASS-II MOLECULES

We have studied the consequences of invariant chain (Ii) and DM expres sion on major histocompatibility complex (MHC) class II function. Ii h as a number of discrete functions in the biology of class II, includin g competitive blocking of peptide binding in the endoplasmic reticulum and enhancing localization in the endocytic compartments. DM is thoug ht to act primarily in endosomes to promote dissociation of the Ii-der ived (CLIP) peptide from the class II antigen-binding pocket and subse quent peptide loading. In this study, we have evaluated the functional role of Ii and DM by examining their impact on surface expression of epitopes recognized by a large panel of alloreactive T cells. We find most epitopes studied are influenced by both Ii and DM. Most strikingl y, we. find that surface expression of a significant fraction of pepti de-class II complexes is extinguished, rather than enhanced, by DM exp ression within the APC. The epitopes antagonized by DM do not appear t o be specific for CLIP. Finally, we found that DM. was also able to ex tinguish recognition of a defined peptide derived hom the internally s ynthesized H-2L(d) protein. Thus, rather than primarily serving in the removal of CLIP, DM may have a more generalized function of editing t he array of peptides that are presented by class II. This editing can be either positive or negative, suggesting that DM plays a specifying role in the display of peptides presented to CD4 T cells.