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14 iNKT Cells1
* Department of Dermatology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115;
Department of Pediatric Immunology, University Medical Center Utrecht, Wilhelmina Children’s Hospital, Utrecht, The Netherlands;
Department of Developmental Biology, Utrecht University, Utrecht, The Netherlands;
Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands; and
¶ School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom
The positive selection of V
14 invariant (i)NKT cells in mice requires CD1d-mediated Ag presentation by CD4+CD8+ thymocytes. Maturation of newly selected iNKT cells continues in the periphery and also involves CD1d expression. CD1d molecules acquire Ags for presentation in endosomal compartments, to which CD1d molecules have access through an intrinsic CD1d-encoded tyrosine motif and by association with the class II MHC chaperone, invariant chain. In this study, we report the generation of mice in which all CD1d is replaced by CD1d-enhanced yellow fluorescent fusion protein (EYFP). CD1d-EYFP molecules are stable, present lipid Ags, and have near normal subcellular distribution. CD1d-EYFP molecules mediated positive selection of V14 iNKT cell precursors at decreased efficiency, caused a delay in their terminal maturation, and did not invoke V14 iNKT cell effector function as wild-type CD1d could. Using these mice, we show that the intrinsic CD1d-encoded sorting motif mediates thymic selection and activation of V14 iNKT cells by professional APCs, while for peripheral terminal differentiation the intrinsic CD1d sorting motif is dispensable.
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 a predoctoral fellowship from the Boehringer Ingelheim Fonds (to F.S.), the Harvard Skin Disease Research Center, NWO-Veni Grant and RO1-AR052810 (to M.B.). G.S.B. acknowledges support from The Medical Research Council, The Wellcome Trust, and James Bardrick in the form of a Personal Research Chair and a Royal Society Wolfson Research Merit Award.
F.S. and M.B. designed research; F.S., M.B., and D.S. performed research; N.V. and G.B. contributed new reagents; F.S. and M.B. analyzed data; and F.S. and M.B. wrote the paper.
2 Address correspondence and reprint requests to Dr. Marianne Boes, Department of Pediatric Immunology, University Medical Center Utrecht, Wilhelmina Children’s Hospital, Utrecht, The Netherlands. E-mail address: mboes{at}umcutrecht.nl
3 Abbreviations used in this paper: Ii, invariant chain; i, invariant; GalCer, -galactosylceramide; DP, double-positive; DC, dendritic cell; EYFP, enhanced yellow fluorescent fusion protein; Gal(1
2)GalCer, galactosyl(12) galactosylceramide; DN, double negative; WT, wild type.
4 The online version of this article contains supplemental material.
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