Early endosomal maturation of MHC class II molecules independently of cysteine proteases and H-2DM

Major histocompatibility complex (PI;IHC) class II molecules bind and prese nt to CD4(+) T cells peptides derived from endocytosed antigens. Class II m olecules associate in the endoplasmic reticulum with invariant chain (Ii), which (i) mediates the delivery of the class II-Ii complexes into the endoc ytic compartments where the antigenic peptides are generated; and (ii) bloc ks the peptide-binding site of the class II molecules until they reach thei r destination. Once there, Ii must be removed to allow peptide binding. The bulk of Ii-class II complexes reach late endocytic compartments where Ii i s eliminated in a reaction in which the cysteine protease cathepsin S and t he accessory molecule H-2DM play an essential role. Here, we here show that Ii is also eliminated in early endosomal compartments without the interven tion of cysteine proteases or H-2DR I. The Ii-free class II molecules gener ated by this alternative mechanism first bind high molecular weight polypep tides and then mature into peptide-loaded complexes.