Cathepsin S controls the trafficking and maturation of MHC class II molecules in dendritic cells

Before a class II molecule can be loaded with antigenic material and reach the surface to engage CD4+ T cells, its chaperone, the class II-associated invariant chain (Ii), is degraded in a stepwise fashion by proteases in end ocytic compartments, We have dissected the role of cathepsin S (CatS) in th e trafficking and maturation of class II molecules by combining the use of dendritic cells (DC) from CatS(-/-) mice with a new active site-directed pr obe for direct visualization of active CatS. Our data demonstrate that CatS is active along the entire endocytic route, and that cleavage of the lysos omal sorting signal of Ii by CatS can occur there in mature DC. Genetic dis ruption of CatS dramatically reduces the flow of class II molecules to the cell surface. In CatS(-/-) DC, the bulk of major histocompatibility complex (MHC) class II molecules is retained in late endocytic compartments, altho ugh paradoxically, surface expression of class II is largely unaffected. Th e greatly diminished but continuous flow of class II molecules to the cell surface, in conjunction with their long half-life, can account for the latt er observation. We conclude that in DC, CatS is a major de terminant in the regulation of intracellular trafficking of MHC class II molecules.