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

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...

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Veröffentlicht in:Nature communications 2017-03, Vol.8 (1), p.14715-14715, Article 14715
Hauptverfasser: Barthels, Christian, Ogrinc, Ana, Steyer, Verena, Meier, Stefanie, Simon, Ferdinand, Wimmer, Maria, Blutke, Andreas, Straub, Tobias, Zimber-Strobl, Ursula, Lutgens, Esther, Marconi, Peggy, Ohnmacht, Caspar, Garzetti, Debora, Stecher, Bärbel, Brocker, Thomas
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Sprache:eng
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Zusammenfassung: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. CD103 + dendritic cells induce iTreg cells to maintain immune balance in the gut, but how CD40-signalling regulates this process is unclear. Here the authors show that mice with constitutive CD11c-specific CD40-signalling have altered CD103 + dendritic cell migration, reduced iTreg cell induction, and fatal colitis.
ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms14715