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.
Highlights
Immune homeostasis in intestinal tissues depends on the generation of regulatory T (Treg) cells
This interpretation is further strengthened by the finding that CD11c þ MHCII þ dendritic cells (DCs) sorted from the lamina propria (LP) after anti-CD40 treatment upregulate expression of mRNA for CCR7 (Fig. 1c), which is a requirement for migration of CD103 þ DCs from LP to mLNs25
Since the increase of CD103 þ DCs in mesenteric lymph nodes (mLNs) is only transient, we investigated the fate of these cells and analysed DCs in mLNs for the presence of activated caspase 3 as a marker for apoptosis (Fig. 1d)
Summary
Immune homeostasis in intestinal tissues depends on the generation of regulatory T (Treg) cells. A large fraction of colonic Foxp[3] þ Treg cells is induced by the microbiota to express retinoic acid receptor-related orphan gt (RORgt)[7,8], and the deletion of RORgt þ iTreg cells caused increased production of intestinal IL-17A and interferon-g (IFN-g) in one study[8] or elevated type 2 helper T (Th2)-responses in another study[7] Both studies demonstrated the importance of RORgt þ Foxp[3] þ iTregs to suppress T effector cells in the gut, the precise antiinflammatory role of RORgt þ Foxp[3] þ iTreg cells is unclear[9]. Studies revealed precise roles of the distinct DC subsets showing that CD103 þ CD11b À DCs migrating from LP to draining LN, but not sessile CD64 þ monocytederived cells are essential for the induction of iTreg cells[18]
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