title: Macrophage-mediated gliadin degradation and concomitant IL-27 production drive IL-10- and IFN-γ-secreting Tr1-like-cell differentiation in a murine model for gluten tolerance.
abstract: Celiac disease is caused by inflammatory T-cell responses against the insoluble dietary protein gliadin. We have shown that, in humanized mice, oral tolerance to deamidated chymotrypsin-digested gliadin (CT-TG2-gliadin) is driven by tolerogenic interferon (IFN)-γ- and interleukin (IL)-10-secreting type 1 regulatory T-like cells (Tr1-like cells) generated in the spleen but not in the mesenteric lymph nodes. We aimed to uncover the mechanisms underlying gliadin-specific Tr1-like-cell differentiation and hypothesized that proteolytic gliadin degradation by splenic macrophages is a decisive step in this process. In vivo depletion of macrophages caused reduced differentiation of splenic IFN-γ- and IL-10-producing Tr1-like cells after CT-TG2-gliadin but not gliadin peptide feed. Splenic macrophages, rather than dendritic cells, constitutively expressed increased mRNA levels of the endopeptidase Cathepsin D; macrophage depletion significantly reduced splenic Cathepsin D expression in vivo and Cathepsin D efficiently degraded recombinant γ-gliadin in vitro. In response to CT-TG2-gliadin uptake, macrophages enhanced the expression of Il27p28, a cytokine that favored differentiation of gliadin-specific Tr1-like cells in vitro, and was previously reported to increase Cathepsin D activity. Conversely, IL-27 neutralization in vivo inhibited splenic IFN-γ- and IL-10-secreting Tr1-like-cell differentiation after CT-TG2-gliadin feed. Our data infer that endopeptidase mediated gliadin degradation by macrophages and concomitant IL-27 production drive differentiation of splenic gliadin-specific Tr1-like cells.
authors: Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: M A
authors: MA
authors: van Leeuwen
authors: Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: L M M
authors: LMM
authors: Costes
authors: Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: L A
authors: LA
authors: van Berkel
authors: Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: Y
authors: Y
authors: Simons-Oosterhuis
authors: Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.|Center for Immune Regulation, Institute of Immunology, University of Oslo and Oslo University Hospital -Rikshospitalet, Oslo, Norway.
authors: M F
authors: MF
authors: du Pré
authors: Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: A E
authors: AE
authors: Kozijn
authors: Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: H C
authors: HC
authors: Raatgeep
authors: Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: D J
authors: DJ
authors: Lindenbergh-Kortleve
authors: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors: N
authors: N
authors: van Rooijen
authors: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors: F
authors: F
authors: Koning
authors: Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: J N
authors: JN
authors: Samsom
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000378:metabolism; D020059:Cathepsin E / Q000378:metabolism; D002446:Celiac Disease / Q000276:immunology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005903:Gliadin / Q000378:metabolism*; D005983:Glutens / Q000276:immunology; D006683:HLA-DQ Antigens / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D064094:Interleukin-27 / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016513:Mice, SCID; D059748:Proteolysis; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; D064094:Interleukin-27; D011948:Receptors, Antigen, T-Cell; D016753:Interleukin-10; D005983:Glutens; D007371:Interferon-gamma; D005903:Gliadin; D020059:Cathepsin E