The ɑßIi complexes exit the endoplasmic reticulum (ER), traverse the Golgi, and enter the endocytic compartments directly or after transient expression at the plasma membrane. The relative amount of ɑßIi complexes that intersect the endocytic route at early endosomal, late endosomal, or lysosomal stations probably varies among differet types of APC. Conversion of ɑßIi into ɑß-peptide can occur along the entire endocytic route. A mechanism independent of cysteine proteases and H-2DM/HLA-DM eliminates Ii in early endosomes (EE), enabling some ɑß dimers first to capture high molecular weight polypeptides and then to mature into ɑß-peptide. Most ɑßIi complexes proceed to later compartments where Ii is eliminated in a stepwise manner by as yet unknown proteases to generate ɑß-Iip10. This complex is transformed into ɑß-CLIP by the action of Cat S (in B cells and DC)/Cat L (in TEC). CLIP is then substituted by antigenic peptides in a reaction catalyzed by H-2DM/HLA-DM and H-2DO/HLA-DO. A schematic representation of the ɑßIi/Iip41, ɑß-Iip10, and ɑß-CLIP complexes is shown at the bottom. antigen processing machinery, it is upregulated by inter- of class II at the plasma membrane of Cat SJ/J APC. Development of CD4+ T cells in Cat SJ/J mice was feron-(Chapman et al., 1997). Incubation of APC with the Cat S inhibitor N-morpholinurea-leucyl-homophenyl- normal. The antibody responses of Cat SJ/J mice to OVA or alanyl-vinylsulfone-phenyl (LHVS) resulted in accumulation of class II ɑß dimers associated with the degrada- HEL injected in complete Freund’s adjuvant, or to collagen type II, were diminished (Nakagawa et al., 1999; Shi tion intermediate Iip10 (Figure 1). The ɑß-Iip10 complex could then be converted in vitro into ɑß-CLIP by diges- et al., 1999). Compared to the wild-type controls, Cat SJ/J mice were more deficient in secreting anti-OVA tion with recombinant Cat S (Riese et al., 1996), supporting a key role for Cat S in antigen presentation. This role and anti-HEL IgG2 and IgG3 than IgM or IgG1. This correlated with a lack of germinal centers in the mutant has been assessed more directly by analysis of Cat S knockout mice. animals. Perhaps the APC that participates at the initial stages of the humoral response (characterized by the In B cells and dendritic cells (DC) deficient in Cat S, degradation of Ii was interrupted at the Iip10 stage, secretion of IgM and IgG1)—presumably a DCJ is less dependent on Cat S than are B cells, which must present resulting in accumulation of ɑß-Iip10 complexes (Nakagawa et al., 1999; Shi et al., 1999). Some of these com- antigenic peptides to T helper cells to induce the formation of the germinal centers and therefore the secretion plexes were slowly converted into ɑß-peptide and expressed at the cell surface, either because Iip10 was of IgG2 and IgG3 (Liu and Arpin, 1997). Indeed, differences in protease use may be a rule degraded by (an) other protease (s), or because Iip10 could be removed slowly without further degradation. among distinct APC: macrophages can overcome the absence of Cat S because they express other enzymes In addition, the ɑß-Iip10 complexes were transported gradually to the plasma membrane, a surprising result absent from or low in B cells and DC, Cat L (Nakagawa et al., 1999) or Cat F (Shi et al., 2000). Thymic epithelial because the cytoplasmic portion of Ii (and of Iip10) contains signals for retention in intracellular compartments cells (TEC), responsible for positive selection of thymocytes (Laufer et al., 1996), rely only on Cat L to cleave (Bakke and Dobberstein, 1990; Amigorena et al., 1995; Brachet et al., 1997). The contribution of both ɑß-peptide Iip10 …