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

doi:10.1038/ncomms14715

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

Cardiovascular Medicine

Research output: Contribution to journal › Article › peer-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 language	English (US)
Article number	14715
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14715
State	Published - Mar 9 2017

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Barthels, C., Ogrinc, A., Steyer, V., Meier, S., Simon, F., Wimmer, M., Blutke, A., Straub, T., Zimber-Strobl, U., Lutgens, E., Marconi, P., Ohnmacht, C., Garzetti, D., Stecher, B., & Brocker, T. (2017). CD40-signalling abrogates induction of ROR3t + Treg cells by intestinal CD103 + DCs and causes fatal colitis. Nature communications, 8, Article 14715. https://doi.org/10.1038/ncomms14715

Barthels, C, Ogrinc, A, Steyer, V, Meier, S, Simon, F, Wimmer, M, Blutke, A, Straub, T, Zimber-Strobl, U, Lutgens, E, Marconi, P, Ohnmacht, C, Garzetti, D, Stecher, B & Brocker, T 2017, 'CD40-signalling abrogates induction of ROR3t + Treg cells by intestinal CD103 + DCs and causes fatal colitis', Nature communications, vol. 8, 14715. https://doi.org/10.1038/ncomms14715

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title = "CD40-signalling abrogates induction of ROR3t + 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 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.",

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AU - Barthels, Christian

AU - Ogrinc, Ana

AU - Steyer, Verena

AU - Meier, Stefanie

AU - Simon, Ferdinand

AU - Wimmer, Maria

AU - Blutke, Andreas

AU - Straub, Tobias

AU - Zimber-Strobl, Ursula

AU - Lutgens, Esther

AU - Marconi, Peggy

AU - Ohnmacht, Caspar

AU - Garzetti, Debora

AU - Stecher, Bärbel

AU - Brocker, Thomas

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CD40-signalling abrogates induction of ROR3t + Treg cells by intestinal CD103 + DCs and causes fatal colitis

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