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Route of Uptake of Palmitoylated Encephalitogenic Peptides of Myelin Proteolipid Protein by Antigen-Presenting Cells: Importance of the Type of Bond between Lipid Chain and Peptide and Relevance to Autoimmunity¹

Nadège A. Pfender^*,, Sylvie Grosch, Guy Roussel, Marc Koch, Elisabeth Trifilieff^2,* and Judith M. Greer^2,3,

^* Chimie Organique des Substances Naturelles, Unité Mixte de Recherche 7177, Centre National de la Recherche Scientifique/Université Louis Pasteur, Institut National de la Santé et de la Recherche Médicale U575, Centre de Neurochimie, Strasbourg, and Centre d’Imagerie, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université Louis Pasteur, Illkirch, France; and Neuroimmunology Research Unit, School of Medicine, University of Queensland, Royal Brisbane and Women’s Hospital, Brisbane, Australia

Previously, we have shown that thiopalmitoylation of peptides of myelin proteolipid protein, as occurs naturally in vivo, increases their ability to induce experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis, and skews the autoimmune response toward a CD4⁺-mediated response. In contrast, the same peptide, when synthesized with a stable amide bond between peptide and lipid, inhibits experimental autoimmune encephalomyelitis and skews the response toward a CD8⁺ response. The aim of the current study was to determine the mechanisms responsible for these observations. We show that proteolipid protein lipopeptides, when synthesized with a thioester bond between the lipid and the peptide, are taken up into APCs via an actin-independent endocytic route, the thioester bond is cleaved in the endosome, and the peptide is subsequently displayed on the surface of the APC in the context of MHC class II. The same peptide, when synthesized with the lipid attached via a stable amide bond, rapidly enters into the cytoplasm of the APC and forms micelles; however, the bond between peptide and lipid is not cleaved, and the micelles travel via the endoplasmic reticulum to complex with MHC class I. These findings have implications for vaccine development and for the development of MHC class II-restricted autoimmune diseases, as many human autoantigens thus far identified are thioacylated.

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 the French Embassy in Australia, the Ministère Délégué à l’Enseignement Supérieur et à la Recherche, and the Groupe Français des Peptides et Protéines.

² E.T. and J.M.G. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Judith Greer, University of Queensland, Royal Brisbane and Women’s Hospital, Herston, C Floor, Clinical Sciences Building, Brisbane, Queensland 4029, Australia. E-mail address: j.greer{at}uq.edu.au

⁴ Abbreviations used in this paper: PLP, proteolipid protein; MS, multiple sclerosis; EAE, experimental autoimmune encephalomyelitis; PC, peritoneal cell; ER, endoplasmic reticulum; AOTF, acousto-optic tunable filter.