Dendritic cells in intestinal immune regulation - PubMed (original) (raw)
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Dendritic cells in intestinal immune regulation
Janine L Coombes et al. Nat Rev Immunol. 2008 Jun.
Abstract
A breakdown in intestinal homeostasis can result in chronic inflammatory diseases of the gut including inflammatory bowel disease, coeliac disease and allergy. Dendritic cells, through their ability to orchestrate protective immunity and immune tolerance in the host, have a key role in shaping the intestinal immune response. The mechanisms through which dendritic cells can respond to environmental cues in the intestine and select appropriate immune responses have until recently been poorly understood. Here, we review recent work that is beginning to identify factors responsible for intestinal conditioning of dendritic-cell function and the subsequent decision between tolerance and immunity in the intestine.
Figures
Figure 1
Role of Vitamin A metabolites in intestinal DC function. Intestinal DCs promoted expression of gut homing receptors on lymphocytes, peripheral generation of Foxp3+ Treg and class switching to IgA. Retinoic acid plays an important role in all of these processes. Peyer's patch DCs and MLN DCs arriving from the intestine express enzymes that allow them to metabolise retinoic acid, perhaps from retinol carried in the serum or stored in the intestine. Alternatively DCs may transport retinoic acid metabolised from dietary carotenoids or other vitamin A derivatives by IEC to lymphoid tissues. Retinoic acid induces expression of the gut homing receptors, CCR9 and α4β7, on T cells. It has an enhancing effect on TGFβ mediated induction of Foxp3 and synergises with IL-6 or IL-5 to mediate class switching to IgA.
Figure 2
Conditioning of DCs in the intestine. The functional properties of intestinal DCs are altered by factors present in the local environment. Activation of NFκB in IEC, perhaps as a result of the commensal flora signalling through TLR, enhances their production of APRIL and TSLP. TSLP and other epithelial cell derived factors can act on DC to downregulate IL-12/23p40 production in response to bacterial stimulation. DC conditioned in this way preferentially drive classical Th2 responses. IL-10 and TGFβ may also play a role in limiting the responsiveness of intestinal DCs to bacterial or other activation signals. These cytokines may derive from multiple sources, though there may be an autocrine effect of TGFβ produced by DC in response to epithelial derived signals, including retinoic acid. Bacterial products may also act directly on DCs to alter their function, for example through induction of enzymes involved in the metabolism of vitamin A. Defective conditioning of DCs in the intestine may contribute to the pathogenesis of IBD.
Figure 3
Response of intestinal DCs to infection. (a) In the steady state, DCs resident in the intestine are conditioned by epithelial cell derived factors and promote the differentiation of Foxp3+ Treg and IgA secreting B cells upon migration to the MLN. This may occur following sampling of the commensal flora or in response to self-antigens derived from the intestinal epithelium. A small number of DC may also be recruited that escape conditioning and drive Th1 or Th17 responses. These DC may share a precursor with other DC resident in the intestine in the steady state, but encounter bacterial products or other stimuli before conditioning can take place, or they may derive from distinct precursors and be refractory to conditioning. These cells could act as sentinels for the presence of pathogenic species, or mount responses aimed at controlling the commensal flora. (b) In contrast to the commensal flora, some pathogenic species possess virulence factors that allow them to invade the intestinal epithelium and subvert immune responses to enhance their replication. Invasion of the epithelium leads to activation of cytosolic PRR and enhanced production of chemokines and pro-inflammatory cytokines. Neutrophils, macrophages and DC precursors are recruited to the site and become activated by a combination of signals from pathogens and pro-inflammatory cytokines and chemokines. Whether these DC precursors are shared with populations of DC present in the steady state remains unclear. Although DCs resident in the tissues prior to infection may not take on pro-inflammatory function, it is possible that their ability to promote regulatory T cell differentiation may be impeded. Pathogenic microbes may also reach CD103− DC resident in the LN which are capable of driving Th1 responses, likely as a result of not being conditioned in the intestine.
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