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* Department of Dermatology, University Hospital, Erlangen, Germany;
Institute for Medical Microbiology, Immunology, and Hygiene, Technical University, Munich, Germany;
Clinical Cooperation Group "Antigen-Specific Immunotherapy," GSF-National Research Center of Environment and Health and Technical University, Munich, Germany;
Department of Medical Informatics, Biometry and Epidemiology, University Hospital, Erlangen, Germany; and
¶ Molecular Biomedicine, Swiss Federal Institute of Technology, Zurich-Schlieren, Switzerland
Dendritic cells (DC) are key regulators of T cell immunity and tolerance. NKT cells are well-known enhancers of Th differentiation and regulatory T cell function. However, the nature of the DC directing T and NKT cell activation and polarization as well as the role of the respective CD1d Ags presented is still unclear. In this study, we show that peptide-specific CD4+IL-10+ T cell-mediated full experimental autoimmune encephalomyelitis (EAE) protection by TNF-treated semimatured DCs was dependent on NKT cells recognizing an endogenous CD1d ligand. NKT cell activation by TNF-matured DCs induced high serum levels of IL-4 and IL-13 which are absent in NKT cell-deficient mice, whereas LPS plus anti-CD40-treated fully mature DCs induce serum IFN-
. In the absence of IL-4R
chain signaling or NKT cells, no complete EAE protection was achieved by TNF-DCs, whereas transfer of NKT cells into J281–/– mice restored it. However, activation of NKT cells alone was not sufficient for EAE protection and early serum Th2 deviation. Simultaneous activation of NKT cells and CD4+ T cells by the same DC was required for EAE protection. Blocking experiments demonstrated that NKT cells recognize an endogenous glycolipid presented on CD1d on the injected DC. Together, this indicates that concomitant and interdependent presentation of MHC II/self-peptide and CD1d/self-isoglobotrihexosylceramide to T and NKT cells by the same partially or fully matured DC determines protective and nonprotective immune responses in EAE.
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1 This work was supported by the Deutsche Forschungsgemeinschaft with Grants LU851/1-2 and SFB 643 (to M.B.L.) and the ELAN Fonds of the University of Erlangen (to C.W.).
2 Address correspondence and reprint requests to Dr. Manfred B. Lutz, at the current address: Institute for Virology and Immunology, University of Wuerzburg, Versbacherstrasse 7, D-97078 Wuerzburg, Germany; E-mail address: m.lutz{at}vim.uni-wuerzburg.de or Dr. Carsten Wiethe, Department of Dermatology, University Hospital, Hartmannstrasse 14, 91052 Erlangen, Germany; E-mail address: carsten.wiethe{at}derma.imed.uni-erlangen.de
3 Abbreviations used in this paper: DC, dendritic cell; Tr1, regulatory type 1 T; EAE, experimental autoimmune encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; iGb3, isoglobotrihexosylceramide; -GalCer, -galactosylceramide; tg, transgenic; BM, bone marrow; IB4, Griffonia simplicifolia-derived isolectin B4; WT, wild type.
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