The Journal of Experimental Medicine
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Published online 13 October 2003 doi:10.1084/jem.20030143
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© Rockefeller University Press, 0022-1007/2003/10/1133 $5.00
The Journal of Experimental Medicine, Volume 198, Number 8, 1133-1146

The Adaptor Protein AP-3 Is Required for CD1d-Mediated Antigen Presentation of Glycosphingolipids and Development of V{alpha}14i NKT Cells

Dirk Elewaut1, Anna P. Lawton1, Niranjana A. Nagarajan1,2, Emanual Maverakis1, Archana Khurana1, Stefan Höning3, Chris A. Benedict1, Eli Sercarz1, Oddmund Bakke4, Mitchell Kronenberg1,2 and Theodore I. Prigozy1

1 La Jolla Institute for Allergy and Immunology, San Diego, CA 92121
2 Division of Biology, University of California San Diego, La Jolla, CA 92093
3 Biochemistry II, University of Göttingen, Göttingen 37073, Germany
4 Center for Vaccinology and Immunotherapy, Department of Biology, University of Oslo, Oslo NO-0316, Norway

Address correspondence to Mitchell Kronenberg, La Jolla Institute for Allergy and Immunology, 10355 Science Center Dr., San Diego, CA 92121. Phone: (858) 678-4540; Fax: (858) 678-4595; email: mitch{at}liai.org

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.

Key Words: intracellular localization • trafficking • lipid antigen • lymphocyte selection • MHC II trafficking pathway


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