CD40-signalling abrogates induction of ROR3t + 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, Thomas Brocker

Research output: Contribution to journalArticlepeer-review

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 3t + (ROR3t +) 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 ROR3t + 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.

Original languageEnglish (US)
Article number14715
JournalNature communications
Volume8
DOIs
StatePublished - Mar 9 2017

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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