CD40-signalling abrogates induction of RORγt+ Treg cells by intestinal CD103+ DCs and causes fatal colitis

Christian Barthels, Ana Ogrinc, Verena Steyer, Stefanie Meier, Ferdinand Simon, Maria Wimmer, Andreas Blutke, Tobias Straub, Ursula Zimber-Strobl, Esther Lutgens, Peggy Marconi, Caspar Ohnmacht, Debora Garzetti, Bärbel Stecher and Thomas Brocker ()
Additional contact information
Christian Barthels: Institute for Immunology, LMU Munich
Ana Ogrinc: Institute for Immunology, LMU Munich
Verena Steyer: Institute for Immunology, LMU Munich
Stefanie Meier: Institute for Immunology, LMU Munich
Ferdinand Simon: Institute for Immunology, LMU Munich
Maria Wimmer: Center of Allergy Environment (ZAUM), Helmholtz Center and TU Munich
Andreas Blutke: Section of Animal Pathology, LMU Munich
Tobias Straub: Bioinformatics core unit, BMC, LMU Munich
Ursula Zimber-Strobl: Helmholtz Zentrum München, Research Unit Gene Vectors
Esther Lutgens: Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, LMU Munich
Peggy Marconi: University of Ferrara
Caspar Ohnmacht: Center of Allergy Environment (ZAUM), Helmholtz Center and TU Munich
Debora Garzetti: Max von Pettenkofer Institute of Hygiene and Medical Microbiology, German Center for Infection Research (DZIF), Partner Site Munich, LMU Munich
Bärbel Stecher: Max von Pettenkofer Institute of Hygiene and Medical Microbiology, German Center for Infection Research (DZIF), Partner Site Munich, LMU Munich
Thomas Brocker: Institute for Immunology, LMU Munich

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14715

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