title: Multivesicular bodies in intestinal epithelial cells: responsible for MHC class II-restricted antigen processing and origin of exosomes.
abstract: In normal conditions intestinal epithelial cells (IECs) constitutively stimulate regulatory CD4(+) T cells. However, in Crohn's disease (CD), this major histocompatibility complex (MHC) class II-restricted antigen presentation results in stimulation of proinflammatory CD4(+) T cells. We hypothesized that these alternative functions might be mediated by differential sorting and processing of antigens into distinct MHC II-enriched compartments (MIICs). Accordingly, we analysed the endocytic pathways of lumenally applied ovalbumin (OVA) in IECs of the jejunum and ileum of wild-type (WT) and TNFDeltaARE/WT mice that develop a CD-resembling ileitis. Using quantitative reverse transcription polymerase chain reaction, we found that messenger RNA levels of interferon-gamma, tumour necrosis factor-alpha, interleukin-17 and interleukin-10 were significantly up-regulated in the inflamed ileum of TNFDeltaARE/WT mice, confirming CD-like inflammation. Fluorescence and immunoelectron microscopy revealed the presence of MHC II and invariant chain throughout the late endocytic compartments, with most molecules concentrated in the multivesicular bodies (MVB). OVA was targeted into MVB and, in contrast to other MIICs, accumulated in these structures within 120 min of exposure. The IEC-specific A33 antigen localized to internal vesicles of MVB and A33/class II-bearing exosomes were identified in intercellular spaces. Remarkably, the expression pattern of MHC II/invariant chain molecules and the trafficking of OVA were independent of mucosal inflammation and the specific region in the small intestine. MVB seem to be principally responsible for class II-associated antigen processing in IECs and to constitute the origin of MHC II-loaded exosomes. The distinctive functions of IECs in antigen presentation to CD4(+) T cells might arise as a result of differential processing within the MVB identified here.
authors: Department of Internal Medicine I, University Hospital of Schleswig-Holstein, Lübeck, Germany. juergen.buening@uk-sh.de
authors: Jürgen
authors: J
authors: Büning
authors: Dorthe
authors: D
authors: von Smolinski
authors: Kianush
authors: K
authors: Tafazzoli
authors: Klaus-Peter
authors: KP
authors: Zimmer
authors: Stephan
authors: S
authors: Strobel
authors: Maria
authors: M
authors: Apostolaki
authors: George
authors: G
authors: Kollias
authors: Joan K
authors: JK
authors: Heath
authors: Diether
authors: D
authors: Ludwig
authors: Andreas
authors: A
authors: Gebert
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000944:Antigens, Differentiation, B-Lymphocyte / Q000032:analysis; D001692:Biological Transport; D003424:Crohn Disease / Q000276:immunology; D016207:Cytokines / Q000032:analysis / Q000235:genetics; D004195:Disease Models, Animal; D011992:Endosomes / Q000276:immunology* / Q000648:ultrastructure; D004847:Epithelial Cells / Q000276:immunology / Q000648:ultrastructure; D055354:Exosomes / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000032:analysis / Q000276:immunology*; D007082:Ileum; D007413:Intestinal Mucosa / Q000276:immunology* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D016253:Microscopy, Immunoelectron; D010047:Ovalbumin; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D014409:Tumor Necrosis Factor-alpha; C045084:invariant chain; D010047:Ovalbumin