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* Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706; and
School of Biosciences, University of Birmingham, Birmingham, United Kingdom
CD1d molecules present both self Ags and microbial lipids to NKT cells. Previous studies have established that CD1d lysosomal trafficking is required for presentation of autoantigens to murine invariant NKT cells. We show in this study that this is not necessary for autoantigen presentation by human CD1d, but significantly affects the presentation of exogenous Ags. Wild-type and tail-deleted CD1d molecules stimulated similar autoreactive responses by human NKT clones, whereas presentation of exogenous lipids by tail-deleted CD1d was highly inefficient. Chloroquine treatment markedly inhibited exogenous Ag presentation by wild-type CD1d transfectants, but did not affect NKT autoreactive responses. Conversely, APC expression of HLA-DR
and the invariant chain (Ii) was associated with faster internalization of CD1d into the endocytic system and enhanced CD1d-mediated presentation of exogenous Ags, but did not appear to augment NKT autoreactivity. Knockdown of the Ii by small interfering RNA resulted in reduced CD1d surface expression and slower internalization in HLA-DR+ APCs, but not HLA-DR– APCs, demonstrating a direct effect of MHC/Ii complexes on CD1d trafficking. CD1d-mediated presentation of exogenous Ags was much more efficient in immature dendritic cells, which actively recycle MHC class II molecules through the endocytic system, than in mature dendritic cells that have stabilized MHC class II expression at the cell surface, suggesting a physiological role for MHC/Ii complexes in modulating CD1d function. These results indicate that autoantigens and exogenous lipids are acquired by human CD1d at distinct cellular locations, and that Ii trafficking selectively regulates CD1d-mediated presentation of extracellular Ags.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant R01 HL071590 (to J.E.G.) and Department of Defense Grant CM030014 (to X.C. and J.E.G.). J.E.G. is a Pew Scholar in the Biomedical Sciences. G.S.B. acknowledges support from Medical Research Council, Wellcome Trust, and from James Bardrick in the form of a Personnel Research Chair.
2 Address correspondence and reprint requests to Dr. Jenny E. Gumperz, Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, 405 Service Memorial Institute, 1300 University Avenue, Madison, WI 53706. E-mail address: jegumperz{at}wisc.edu
3 Abbreviations used in this paper: ER, endoplasmic reticulum; -GalCer, -galactosylceramide; AP, adaptor protein; DC, dendritic cell; GalGalCer, Gal(1–2)galactosylceramide; iGb3, isoglobotrihexosyl ceramide; Ii, invariant chain; iNKT, invariant NKT; LAMP, lysosomal-associated membrane protein; siRNA, small interfering RNA; DC-SIGN, DC-specific ICAM-grabbing nonintegrin; TD, tail-deleted.
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  X. Chen, X. Wang, G. S. Besra, and J. E. Gumperz Modulation of CD1d-restricted NKT cell responses by CD4 J. Leukoc. Biol., December 1, 2007; 82(6): 1455 - 1465. [Abstract] [Full Text] [PDF]
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