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 (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.