Intestinal Dendritic Cells in Health and Gut Inflammation

Abstract

Dendritic cells (DCs) mediate tolerance to food antigens, limit reactivity to the gut microbiota and are required for optimal response to intestinal pathogens. Intestinal DCs are heterogeneous but collectively generate both regulatory and effector T cell responses. The balance of outcomes is determined by the activity of functionally distinct DC subsets and their modulation by environmental cues. DCs constantly sample luminal content to monitor for pathogens; the significance of the various pathways by which this occurs is incompletely understood. Intestinal DC have distinctive properties shaped by local host, dietary and microbial signals. These properties include the ability to produce all-trans retinoic acid (RA) and imprint gut tropism on T cells they activate. In the steady-state, subsets of intestinal DC are potent generators of inducible Treg, aided by their ability to activate TGFβ and produce RA. However, responses induced by steady-state intestinal DCs are not exclusively regulatory in nature; effector T cells with specificity for commensal bacterial can be found in the healthy mucosa and these can be locally controlled to prevent inflammation. The ability of intestinal DCs to enhance effector responses in infection or sustain inflammation in disease is likely to involve both modulation of the local DC population and recruitment of additional populations. Immune pathways in the pathogenesis of inflammatory bowel disease can be mapped to DCs and in inflamed intestinal tissue, DCs show increased expression of microbial recognition machinery, activation, and production of key immunological mediators. Intestinal DCs may be targeted for disease therapy or to improve vaccine responses.

Keywords: Dendritic cells; antigen sampling; inflammatory bowel disease; intestinal inflammation; lymphocyte homing.

Figure 1

Summary of the origins and properties of intestinal DC. FLT3L-dependent development of cDC gives rise to two major subsets via CDP and committed pre-cDC in the BM. cDC1 are XCR1+ and depend on transcription factors including IRF8 and BATF3; cDC2 are SIRPα+ and depend on transcription factors that include IRF4. Population of the intestinal mucosa may be via an intermediate gut-committed α4β7+ precursor [sometimes termed pre-mucosal (μ) DC] stage (19, 20). In the mouse LP, the cDC2 population comprises two closely related CD11b+ subsets that can be distinguished by the presence or absence of CD103; CD11b+CD103+, found predominately in the SI, are probably derived from the CD11b+CD103– cells under the influence of TGFβ. The cDC1 population is CD11b–CD103+. Similar populations in the human intestine can be identified on the basis of CD103 and SIRPα expression. In the LP they are exposed to conditioning factors (shown as blue arrows) from epithelial cells and other sources which further shape their functional properties. All three subsets have the capacity to migrate to draining lymph nodes to interact with recirculating T cells. Here, production of RA by LP- derived DCs, particularly those expressing CD103, imprints gut tropism on T cells they activate by inducing expression of α4β7 integrin and the chemokine receptor CCR9. Although DCs can induce both Treg and effector T cells, with some specialism across DC subsets, the balance of these outcomes favors regulation in the steady-state. The reader is referred to recent reviews for a more in-depth discussion of intestinal DC subsets (21, 22). HSC, haematopoietic stem cell; CMP, common myeloid progenitor; MDP, monocyte dendritic cell precursor; CDP, common dendritic cell precursor; pDC, plasmacytoid DC; Mono, monocyte; X-present, cross-presentation to CD8+ T cells.

Figure 2

Enhanced generation of effector T cells in response in infection and inflammatory disease. A number of mechanisms act to shift the balance of response induced by intestinal DC to favor the generation of effector responses. These are important for pathogen clearance but if dysregulated may lead to inflammatory disease. Increased exposure to PAMPS and DAMPS, as the result of loss of barrier integrity or tissue penetration by pathogens may be sensed by LP DC populations leading to their activation (A). Altered microbial sensing by epithelial cells due, for instance, to engagement of basolateral PRRs, may change the nature of conditioning factors they produce. Increased DC turnover may reduce exposure to those conditioning factors that normally promote regulatory function in intestinal DC (B). Alternatively, different types of DC, specialized to promote effector responses, may be recruited to the intestine under these conditions. These could be DC-like cells derived from monocytes (C) or possibly “reprogrammed” DC arise as a result of altered differentiation in the BM (D). There may also be a release from the regulatory mechanisms that normally limit effector function within the mucosa, due, for instance to a loss of response to regulatory cytokines like IL-10 or TGFβ or a failure to interact with CX3CR1+ cells that promote regulation (E). The role of DCs on determining responsiveness to these local control mechanisms is not known.