title: CD40-signalling abrogates induction of RORγt+Treg cells by intestinal CD103+DCs and causes fatal colitis.
abstract: Immune homeostasis in intestinal tissues depends on the generation of regulatory T (Treg) cells. CD103+dendritic cells (DCs) acquire microbiota-derived material from the gut lumen for transport to draining lymph nodes and generation of receptor-related orphan γt+(RORγt+) Helios--induced Treg (iTreg) cells. Here we show CD40-signalling as a microbe-independent signal that can induce migration of CD103+DCs from the lamina propria (LP) to the mesenteric lymph nodes. Transgenic mice with constitutive CD11c-specific CD40-signalling have reduced numbers of CD103+DCs in LP and a low frequency of RORγt+Helios-iTreg cells, exacerbated inflammatory Th1/Th17 responses, high titres of microbiota-specific immunoglobulins, dysbiosis and fatal colitis, but no pathology is detected in other tissues. Our data demonstrate a CD40-dependent mechanism capable of abrogating iTreg cell induction by DCs, and suggest that the CD40L/CD40-signalling axis might be able to intervene in the generation of new iTreg cells in order to counter-regulate immune suppression to enhance immunity.
authors.affiliation: Institute for Immunology, LMU Munich, Großhaderner Strasse 9, Planegg-Martinsried 82152, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Barthels
authors.affiliation: Institute for Immunology, LMU Munich, Großhaderner Strasse 9, Planegg-Martinsried 82152, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Ogrinc
authors.affiliation: Institute for Immunology, LMU Munich, Großhaderner Strasse 9, Planegg-Martinsried 82152, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Steyer
authors.affiliation: Institute for Immunology, LMU Munich, Großhaderner Strasse 9, Planegg-Martinsried 82152, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Meier
authors.affiliation: Institute for Immunology, LMU Munich, Großhaderner Strasse 9, Planegg-Martinsried 82152, Germany.
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Simon
authors.affiliation: Center of Allergy Environment (ZAUM), Helmholtz Center and TU Munich, Neuherberg 85764, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Wimmer
authors.affiliation: Section of Animal Pathology, Department of Veterinary Clinical Sciences, LMU Munich, Munich 80539, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Blutke
authors.affiliation: Bioinformatics core unit, BMC, LMU Munich, Großhaderner Strasse 9, Planegg-Munich 82152, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Straub
authors.affiliation: Helmholtz Zentrum München, Research Unit Gene Vectors, Munich 81377, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Zimber-Strobl
authors.affiliation: Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, LMU Munich, Munich 80336, Germany.|Department of Medical Biochemistry, AMC, Amsterdam 1105AZ, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Lutgens
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara 44121, Italy.
authors.forename: Peggy
authors.initials: P
authors.lastname: Marconi
authors.affiliation: Center of Allergy Environment (ZAUM), Helmholtz Center and TU Munich, Neuherberg 85764, Germany.
authors.forename: Caspar
authors.initials: C
authors.lastname: Ohnmacht
authors.affiliation: Max von Pettenkofer Institute of Hygiene and Medical Microbiology, German Center for Infection Research (DZIF), Partner Site Munich, LMU Munich, Munich 80336, Germany.
authors.forename: Debora
authors.initials: D
authors.lastname: Garzetti
authors.affiliation: Max von Pettenkofer Institute of Hygiene and Medical Microbiology, German Center for Infection Research (DZIF), Partner Site Munich, LMU Munich, Munich 80336, Germany.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Stecher
authors.affiliation: Institute for Immunology, LMU Munich, Großhaderner Strasse 9, Planegg-Martinsried 82152, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brocker
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D000069196:Gastrointestinal Microbiome / Q000276:immunology; D039001:Integrin alpha Chains / Q000276:immunology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000276:immunology / Q000382:microbiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D019013:CD40 Antigens; D039001:Integrin alpha Chains; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C091367:alpha E integrins