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 autoimmunity.
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.
Pfender
Nadège A
NA
Chimie Organique des Substances Naturelles, Unité Mixte de Recherche 7177, Centre National de la Recherche Scientifique/Université Louis Pasteur, Strasbourg, France.
Grosch
Sylvie
S
Roussel
Guy
G
Koch
Marc
M
Trifilieff
Elisabeth
E
Greer
Judith M
JM
D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015551:Autoimmunity; D005227:Fatty Acids / Q000737:chemistry; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D008055:Lipids / Q000737:chemistry; D054878:Lipoylation; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D018991:Myelin Proteolipid Protein / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*
D005227:Fatty Acids; D000949:Histocompatibility Antigens Class II; D008055:Lipids; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; C435023:myelin proteolipid protein (139-151)