DISTINCT PEPTIDE LOADING PATHWAYS FOR MHC CLASS-II MOLECULES ASSOCIATED WITH ALTERNATIVE II CHAIN ISOFORMS

Mutant mouse strains expressing either p31 or p41 Ii chain appear equa lly competent with respect to their class II functional activities inc luding Ag presentation and CD4(+) T cell development. To further explo re possibly divergent roles provided by alternative Ii chain isoforms, we compare class II structure and function in double mutants also car rying a null allele at the H2-DM locus. As for DM mutants expressing w ild-type Ii chain, A alpha(b)A beta(b) dimers present in DM-deficient mice expressing either Ii chain isoform appear equally occupied by cla ss II-associated Ii chain-derived peptides (CLIP). Surprisingly, in fu nctional assays, these novel mouse strains exhibit strikingly differen t phenotypes. Thus, DM-deficient mice expressing wild-type Ii chain or p31 alone are both severely compromised in their abilities to present peptides, In contrast, double mutants expressing the p41 isoform disp lay markedly enhanced peptide-loading capabilities, approaching those observed for wild-type mice. The present data strengthen evidence for divergent class II presentation pathways and demonstrate for the first time that functionally distinct roles are mediated by alternatively s pliced forms of the MHC class II-associated Ii chain in a physiologic setting.