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.

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

MARCONI, Peggy Carla Raffaella;
2017

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.
Barthels, C; Ogrinc, A; Steyer, V; Meier, S; Simon, F; Wimmer, M; Blutke, A; Straub, T; Zimber Strobl, U; Lutgens, E; Marconi, Peggy Carla Raffaella; Ohnmacht, C; Garzetti, D; Stecher, B; Brocker, T.
File in questo prodotto:
File Dimensione Formato  
ncomms14715.pdf

accesso aperto

Descrizione: Full text ed
Tipologia: Full text (versione editoriale)
Licenza: Creative commons
Dimensione 1.61 MB
Formato Adobe PDF
1.61 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11392/2368106
Citazioni
  • ???jsp.display-item.citation.pmc??? 16
  • Scopus 26
  • ???jsp.display-item.citation.isi??? 24
social impact