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Immunomodulation by semi-mature dendritic cells: A novel role of Toll-like receptors and interleukin-6

https://doi.org/10.1016/j.ijmm.2009.08.010Get rights and content

Abstract

Dendritic cells (DCs) are key players in activation of the adaptive immune system by their ability of antigen presentation to and priming of T cells. An increasing body of evidence suggests that DCs may also play an important role in induction of tolerance, predominantly by induction of regulatory T cells (Treg). More recently, data have been published on how Toll-like receptor (TLR) ligands and cytokines affect DC differentiation, and how DC subsets might be involved in immunoregulation and tolerance rather than in T cell activation. The most important features of tolerance-inducing DCs appear to be their maturation state and their cytokine secretion pattern. The following types of tolerance-inducing DCs have been reported: immature DCs (DCsim) or DCs in the steady state (DCsst), DCsIL-10, semi-mature DCsTNF-α, semi-mature DCsIL-6. With this review article we would like to discuss the aforementioned types of tolerogenic DCs with a focus on semi-mature DCsIL-6 and discuss their potential role in maintenance of (hepatic or intestinal) immune homeostasis and inflammatory diseases such as inflammatory bowel disease.

Introduction

Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) with important functions in the mucosa-associated immune system. DCs have the unique capacity to stimulate naive T cells and thus are thought to be initiators of T cell responses (Cella et al., 1997). Activation and maturation of DCs is induced by infectious agents and inflammatory products leading to increased expression of co-stimulatory and MHC-II molecules, cytokine production and T cell activation (Pulendran et al., 2001; Taguchi et al., 2002; Huang et al., 2001; Gagliardi et al., 2000; de Jong et al., 2002; Mahanty et al., 2003). In addition to bacterial stimuli, DC maturation is also regulated by cytokines (Reis e Sousa, 2001). An increasing body of evidence suggests that DCs may also play an important role in maintenance of tolerance, predominantly by induction of CD4+ CD25+ Treg. Additionally, data have been published showing that Toll-like receptor (TLR) ligands and cytokines affect DC differentiation, and that DC subsets differentiated by TLR ligation or by a special cytokine environment might be involved in immunoregulation and tolerance rather than in T cell activation. With this review article we would like to discuss the different types of DCs (Fig. 1) that might be involved in immunoregulation and tolerance with a focus on DCs differentiated by exposure to different cytokines.

Section snippets

Immature DCs (DCsim) or DCs in the steady state (DCsst)

DCsim are characterized by low expression of MHC class I and II and co-stimulatory molecules, are present in all peripheral non-inflamed tissues (van den Broek, 2007) and are very efficient in endocytic and phagocytic antigen capture. The maturation of DCsim is inducible by inflammatory stimuli and results in activated and maturated DCs that promote CD4- or CD8-mediated immune responses (Jonuleit et al., 2001). In contrast to maturated and activated DCs, DCsim induce T cell anergy or Treg cells

DCsIL-10

The basic principle for the functional activity of DCs to induce tolerance or respectively immunity is the environmental milieu during the maturation of DCs. Proinflammatory cytokines, bacterial or viral antigens such as lipopolysaccharide (LPS), double-stranded RNA or CpG motifs trigger the maturation of DCsim (Sparwasser et al., 1998; Sallusto et al., 1998; De Smedt et al., 1996; Pierre et al., 1997). Differentiated mature DCs can effectively activate T cells and induce inflammatory effector

Semi-mature DCsTNF-α

Another possible candidate that mediates semi-, partial- or steady-state- DC maturation that stimulates tolerogenic antigen presentation might be TNF-α (Lutz and Schuler, 2002). Semi-mature DCsTNF-α are induced by stimulation of DCsim with TNF-α. Such DCsTNF-α exhibit an increased expression of MHC class II and co-stimulatory molecules, but are only weak producers of proinflammatory cytokines like e. g. IL-1β, IL-6, TNF-α or IL-12 (Lutz and Schuler, 2002; Menges et al., 2002). However DCsTNF-α

Semi-mature DCsIL-6

Il-6 is a potent, pleiotropic, inflammatory cytokine that mediates a plethora of physiological functions (Kamimura et al., 2003; Heinrich et al., 1998; Steelman et al., 2004). IL-6 is known to influence cell growth, differentiation and migration during immune responses, haematopoiesis and inflammation (Hirano, 1998). IL-6 also affects the differentiation of myeloid lineages, including macrophages and DCs (Chomarat et al., 2000; Murphy et al., 2000). In the presence of IL-6, the number of

The role of TLR and microbial compounds for differentiation of DCsIL-6

Recently, we and others described a new type of tolerogenic DCs which are induced by activation of TLR2 or TLR4 including an autocrine/paracrine loop via IL-6 (Fig. 2). This type of DCs shows a semi-mature phenotype characterised by reduced expression of co-stimulatory and MHC class II molecules and has been referred to as semi-mature DCsIL-6. In vitro, semi-mature DCsIL-6 are differentiated in the presence of IL-6 or by stimulation with TLR ligands at low concentrations (Frick et al., 2006;

Signalling events in differentiation of DCsIL-6

Park et al. (2004) showed that in vivo IL-6 plays a major role in maintaining DCsim. They reported that IL-6−/−-mice had increased numbers of mature DCs, as compared to wild-type mice, and suggested that IL-6 might block DC maturation in vivo. In addition, the authors found that STAT3 phosphorylation in DCs was regulated by IL-6 in vivo, and that STAT3 activation was necessary for the IL-6-mediated suppression of activation or maturation of BMDCs. In line with this, the DC-mediated T-cell

Proinflammatory functions of IL-6 in inflammatory bowel diseases

On the other hand, IL-6 secreted from splenic DCs upon TLR stimulation is an important factor of T-cell activation by overcoming Treg-mediated suppression of T-cell proliferation (Pasare and Medzhitov, 2003). Thus, IL-6−/−-mice are severely compromised in their ability to induce T-cell proliferation upon immunisation with ovalbumin and LPS as adjuvant (Pasare and Medzhitov, 2003). Thus, production of IL-6 by DCs in response to TLR ligation during stimulation appears to be critical for T cell

Conclusions

Based on this synopsis of data, we propose a model in which the differentiation of DCsim by the local cytokine environment is embedded as a major component within immune homeostasis. The local cytokine environment might basically be determined by the host endogenous microbiota. The DC semi-maturation by cytokines such as IL-6 seems to represent a unique tolerogenic differentiation state for DCs, which is based on the absence of proinflammatory cytokine production and impaired expression of

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