The adaptor protein AP-3 is required for CD1d-mediated antigen presentation of glycosphingolipids and development of Valpha14i NKT cells.
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.
Elewaut
Dirk
D
La Jolla Institute for Allergy and Immunology, 10355 Science Center Dr., San Diego, CA 92121, USA.
Lawton
Anna P
AP
Nagarajan
Niranjana A
NA
Maverakis
Emanual
E
Khurana
Archana
A
Honing
Stefan
S
Benedict
Chris A
CA
Sercarz
Eli
E
Bakke
Oddmund
O
Kronenberg
Mitchell
M
Prigozy
Theodore I
TI
D033963:Adaptor Protein Complex 3 / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D018949:Antigens, CD1 / Q000235:genetics / Q000276:immunology*; D055610:Antigens, CD1d; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002452:Cell Count; D022801:Complementarity Determining Regions / Q000737:chemistry; D005434:Flow Cytometry; D006028:Glycosphingolipids / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008099:Liver / Q000276:immunology; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D011993:Recombinant Fusion Proteins / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology
D033963:Adaptor Protein Complex 3; D018949:Antigens, CD1; D055610:Antigens, CD1d; D022801:Complementarity Determining Regions; D006028:Glycosphingolipids; D011993:Recombinant Fusion Proteins