Dendritic cells in intestinal homeostasis and disease

Abstract

DCs are specialized APCs that orchestrate innate and adaptive immune responses. The intestinal mucosa contains numerous DCs, which induce either protective immunity to infectious agents or tolerance to innocuous antigens, including food and commensal bacteria. Several subsets of mucosal DCs have been described that display unique functions, dictated in part by the local microenvironment. In this review, we summarize the distinct subtypes of DCs and their distribution in the gut; examine how DC dysfunction contributes to intestinal disease development, including inflammatory bowel disease and celiac disease; and discuss manipulation of DCs for therapy.

Figure 1. DC distribution and function in the LP.

Left: CX3CR1⁺ DCs extend protrusions across the epithelial barrier. These cells also express CD70 and drive the differentiation of Th17 cells via a mechanism dependent on ATP and/or flagellin. CD103⁺ DCs migrate into the draining MLN, where they promote the conversion of Foxp3⁺ Tregs via an RA- and TGF-β–dependent mechanism. Tregs also upregulate the expression of the gut-homing marker α₄β₇. A third population of APCs of non–bone marrow origin expressing CD70⁺ is required for T cell proliferation directly in the LP. Right: The phenotype of CD103⁺ LP DCs is conferred by the local microenvironment, in particular by IECs via the release of TGF-β, RA, and — in the human system — TSLP. CD103⁺ DCs acquire the ability to drive the differentiation of Tregs and to inhibit Th1 and Th17 cell development. Macrophages also limit intestinal inflammation via activation of Tregs and inhibition of the ability of CX3CR1⁺ DCs to drive Th17 cell development. Macrophages retain full antibactericidal activity.

Figure 2. Three non–mutually exclusive possible mechanisms of DC involvement in IBD that lead to an imbalance between Th17/Th1 and Treg cells have been reported.

(A) Involvement of ATP-releasing or flagellated bacteria. An unexpected increase in the number of bacteria releasing ATP or expressing flagellin can lead to the activation of CX3CR1⁺CD70⁺ DCs that favor Th17 cell differentiation (i). (B) Involvement of the local microenvironment. A defect in the release of immunomodulatory factors (e.g., TSLP, TGF-β, and RA) by IECs may lead to a reduction in Treg numbers caused by the failure of conditioning tolerogenic CD103⁺ DCs (ii). Local inflammation may lead to the recruitment of inflammatory DCs; by releasing IL-12 and TNF-α, these inflammatory DCs drive the differentiation of IFN-γ and TNF-α Th1 cells (iii). (C) Involvement of immune cells. Inflammation may also affect the differentiation of tolerogenic macrophages from recruited monocytes, leading to reduction in Treg differentiation and inability to control the activity of CX3CR1⁺CD70⁺ DCs (iv). Th17 or Th1 cells are strongly restimulated in situ by CD70⁺ or OX40L⁺ APCs (v). Both DC types have not been described in humans, but the retention of activated DCs has been shown. The mechanisms in A–C may participate in disease induction by generating an imbalance between Tregs and Th1 or Th17 cells (vi). Th1/Th17 cells release IFN-γ, TNF-α, or IL-17, which contribute to tissue destruction through the release of MMPs by activated fibroblasts and the recruitment of neutrophils. Th1 or inflammatory, DC-derived TNF-α may also increase the endothelial expression of MAdCAM-1, thus favoring the recruitment of α₄β₇⁺ Th1 cells.

Figure 3. Possible role of DCs in celiac disease.

Gluten peptides are transported across the intestinal epithelium via: retrotranscytosis (i), a protected retrotransport of secretory IgA via transferrin receptor CD71, which allows the entry of intact and thus harmful peptides into the intestinal mucosa; by a transcellular route (ii); or by a paracellular route (iii) as a consequence of impaired mucosal integrity. Gluten peptides might also be sampled by DCs extending their protrusions into the lumen (iv). Deamidation of gluten peptides by tissue transglutaminase (tTG) reinforces presentation of gluten peptides by pDCs to T cells in the context of HLA-DQ2 or HLA-DQ8 molecules. Activated, gluten-reactive Th1 cells produce high levels of proinflammatory cytokines (e.g., IFN-γ and IL-21), which promote fibroblast secretion of MMPs responsible for degradation of ECM and basement membrane, and increase the intraepithelial lymphocyte (IEL) cytotoxicity through interaction between the homodimeric NK-activating receptor NFG2D and the MHC class I–related ligands (MIC), thus leading to epithelial cell apoptosis. IFN-α released by activated pDCs perpetuates the inflammatory reaction by inducing Th1 cells to produce IFN-γ. IL-21 and IL-15 produced by DCs and IECs inhibit TGF-β signaling and Treg function. Additionally, through the production of Th2 cytokines, Th2 cells drive the activation and clonal expansion of B cells, which differentiate into plasma cells producing anti-gliadin and anti–tissue transglutaminase antibodies. The latter have proven to be highly valuable in the diagnosis of celiac disease, as they are present in 98% of celiac patients on a gluten-containing diet.