title: MHC II in dendritic cells is targeted to lysosomes or T cell-induced exosomes via distinct multivesicular body pathways.
abstract: Dendritic cells (DCs) express major histocompatibility complex class II (MHC II) to present peptide antigens to T cells. In immature DCs, which bear low cell surface levels of MHC II, peptide-loaded MHC II is ubiquitinated. Ubiquitination drives the endocytosis and sorting of MHC II to the luminal vesicles of multivesicular bodies (MVBs) for lysosomal degradation. Ubiquitination of MHC II is abrogated in activated DCs, resulting in an increased cell surface expression. We here provide evidence for an alternative MVB sorting mechanism for MHC II in antigen-loaded DCs, which is triggered by cognately interacting antigen-specific CD4+ T cells. At these conditions, DCs generate MVBs with MHC II and CD9 carrying luminal vesicles that are secreted as exosomes and transferred to the interacting T cells. Sorting of MHC II into exosomes was, in contrast to lysosomal targeting, independent of MHC II ubiquitination but rather correlated with its incorporation into CD9 containing detergent-resistant membranes. Together, these data indicate two distinct MVB pathways: one for lysosomal targeting and the other for exosome secretion.
authors.affiliation: Faculty of Veterinary Medicine, Department of Biochemistry & Cell Biology, Utrecht University, The Netherlands.
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Buschow
authors.forename: Esther N M
authors.initials: EN
authors.lastname: Nolte-'t Hoen
authors.forename: Guillaume
authors.initials: G
authors.lastname: van Niel
authors.forename: Maaike S
authors.initials: MS
authors.lastname: Pols
authors.forename: Toine
authors.initials: T
authors.lastname: ten Broeke
authors.forename: Marjolein
authors.initials: M
authors.lastname: Lauwen
authors.forename: Ferry
authors.initials: F
authors.lastname: Ossendorp
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
authors.forename: Graça
authors.initials: G
authors.lastname: Raposo
authors.forename: Richard
authors.initials: R
authors.lastname: Wubbolts
authors.forename: Marca H M
authors.initials: MH
authors.lastname: Wauben
authors.forename: Willem
authors.initials: W
authors.lastname: Stoorvogel
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D004591:Electrophoresis, Polyacrylamide Gel; D055354:Exosomes / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D008247:Lysosomes / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D016253:Microscopy, Immunoelectron; D057146:Multivesicular Bodies / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D021381:Protein Transport; D013154:Spleen / Q000166:cytology; D054875:Ubiquitination
chemical_list: D000949:Histocompatibility Antigens Class II