DEGRADATION OF MOUSE INVARIANT CHAIN - ROLES OF CATHEPSIN-S AND CATHEPSIN-D AND THE INFLUENCE OF MAJOR HISTOCOMPATIBILITY COMPLEX POLYMORPHISM

Antigen-presenting cells (APC) degrade endocytosed antigens into pepti des that are bound and presented to T cells by major histocompatibilit y complex (MHC) class II molecules. Class II molecules are delivered t o endocytic compartments by the class II accessory molecule invariant chain (Ii), which itself must be eliminated to allow peptide binding. The cellular location of Ii degradation, as well as the enzymology of this event, are important in determining the sets of antigenic peptide s that will bind to class II molecules. Here, we show that the cystein e protease cathepsin S acts in a concerted fashion with other cysteine and noncysteine proteases to degrade mouse Ii in a stepwise fashion. Inactivation of cysteine proteases results in incomplete degradation o f Ii, but the extent to which peptide loading is blocked by such treat ment varies widely among MHC class II allelic products. These observat ions suggest that, first, class II molecules associated with larger Ii remnants can be converted efficiently to class II-peptide complexes a nd, second, that most class II-associated peptides can still be genera ted in cells treated with inhibitors of cysteine proteases. Surprising ly, maturation of MHC class II in mice deficient in cathepsin D is una ffected, showing that this major aspartyl protease is not involved in degradation of Ii or in generation of the bulk of antigenic peptides.