The Adaptor Protein AP-3 Is Required for CD1d-Mediated Antigen Presentation of Glycosphingolipids and Development of Vα14i NKT Cells

Abstract

Relatively little is known about the pathway leading to the presentation of glycolipids by CD1 molecules. Here we show that the adaptor protein complex 3 (AP-3) is required for the efficient presentation of glycolipid antigens that require internalization and processing. AP-3 interacts with mouse CD1d, and cells from mice deficient for AP-3 have increased cell surface levels of CD1d and decreased expression in late endosomes. Spleen cells from AP-3–deficient mice have a reduced ability to present glycolipids to natural killer T (NKT) cells. Furthermore, AP-3–deficient mice have a significantly reduced NKT cell population, although this is not caused by self-tolerance that might result from increased CD1d surface levels. These data suggest that the generation of the endogenous ligand that selects NKT cells may also be AP-3 dependent. However, the function of MHC class II–reactive CD4+ T lymphocytes is not altered by AP-3 deficiency. Consistent with this divergence from the class II pathway, NKT cell development and antigen presentation by CD1d are not reduced by invariant chain deficiency. These data demonstrate that the AP-3 requirement is a particular attribute of the CD1d pathway in mice and that, although MHC class II molecules and CD1d are both found in late endosomes or lysosomes, different pathways mediate their intracellular trafficking.

Regulation of CD1d expression and function by a herpesvirus infection

“…Further investigation will be required to determine the cause as well as the significance of this difference; however, we suspect it could be due to a differential effect of the MIR proteins on CD1d loading of endogenously versus exogenously derived antigens. CD1d molecules traffic extensively through the endocytic system (49)(50)(51)(52)(53) and are capable of presenting both exogenously derived (54) and endogenously derived antigens (46,55). However, it is not clear in which compartments the relevant physiological ligands of CD1d-restricted T cells are loaded, and it is possible that exogenous and endogenous cellular lipids may be loaded at different sites.…”

Apoptosis‐induced inhibition of CD1d‐mediated antigen presentation: different roles for caspases and signal transduction pathways

“…considering the similarity of the AP-3 molecule (that CD1d1 uses) to the AP-1 and AP-2 adaptor proteins, [46][47][48][49][50] it seems highly probable that AP-3 could similarly be affected by the caspase cascade. An argument could be made suggesting that our results could simply be explained by a reduction in the level of CD1d on the cell surface.…”

The cellular and biochemical rules of lipid antigen presentation

“…What determines CD1c trafficking to one of these compartments and whether CD1c has unique recycling patterns in different cell types is unknown. Mouse CD1d reaches Ly in an AP-3-dependent manner, whereas human CD1d does not form complexes with this adaptor protein [45,46]. CD1e has a very different trafficking route.…”