Fig. 4.

Endosomal recycling of CD1b and pH. CD1 is synthesized in the ER in the presence of a variety of lipid ligands, which help to stabilize the protein-lipid complex. CD1b then is shuttled to the cell surface within the secretory pathway, where further lipid exchange can take place with endogenous or exogenous lipids. CD1b is re-internalized and sorted based on isoform-specific sorting motifs into early endosomes or enter late endosome/lysosomes. Lipids entering with CD1b or from other endosomal compartments can be generated by endosomal co-factors. Acidic pH alters the physical properties of CD1b, which promotes lipid exchange in an editing process that allows lipids with higher affinity for CD1b to be loaded in late endosomes before recycling back to the cell surface. Whereas the ability of cell surface CD1b to bind only short-chain lipids has been long known, spacers now provide a candidate mechanism that explains why short-chain lipids have lower stringency loading requirements: exogenous short-chain lipids would only need to exchange with the superficially seated antigen on top, whereas long-chain lipids would require expulsion of antigens and deeply seated spacers