Function and dysfunction of dendritic cells in autoimmune rheumatic diseases
Introduction
Dendritic cells (DC) are highly specialized antigen-presenting cells (APC) that dictate the outcome of immune responses through the integration of a variety of incoming signals [1], [2]. In humans, conventional DC subsets include the myeloid DC (mDC or DC1) and the plasmacytoid DC (pDC or DC2) [3], [4]. mDC develop from CD11c+HLA-DR+ blood precursors and undergo activation and maturation in response to triggering of Toll-like receptors (TLR), a class of pattern recognition receptors engaged by microbial products [1]. The process of DC maturation is paralleled by the upregulation of major histocompatibility complex (MHC) class II and costimulatory CD80/CD86 molecules and by the production of interleukin (IL)-12. mDC have been mainly involved in the differentiation of T helper type 1 (Th1) cells as a result of high IL-12p70 release [5]. pDC might differentiate either from a common blood DC precursor or from a committed lymphoid progenitor, express CD123, CD4, and CD62L, and secrete type I interferon (IFN) in response to viruses or TLR9 ligands [3], [6]. pDC have been associated with the differentiation of Th0/Th2 cells [7]. In addition, CD40 ligand-activated human pDC induce regulatory T cells (Treg), a nonredundant mechanism for the safeguard of peripheral T-cell tolerance [8]. More recently, a remarkable functional plasticity of DC has been highlighted in a variety of experimental models, and both DC1 and DC2 may have the ability to induce Th1 and Th2 responses depending upon the experimental conditions.
The ability of DC to induce tolerance was initially demonstrated by experiments on immature mDC residing in peripheral lymphoid tissues [9], [10]. Under steady-state conditions, immature DC capture apoptotic bodies arising from cell turnover and, after migration to the draining lymph nodes, silence T cells to self-antigens [11]. Mechanistically, short-lived, migratory DC might transfer tissue-derived peptides to longer-lived tolerogenic DC. Interestingly, self-antigen transport, processing, and presentation for tolerance induction by DC require partial maturation [12]. In the absence of inflammation or TLR triggering, DC will not produce IL-12 and will be arrested at a semimature stage (Fig. 1). Also, DC residence in a tolerizing milieu (e.g., in mucosal or immune privileged sites) affects their capacity of priming T cells toward a regulatory profile. The Treg subsets induced by immature mDC and CD40 ligand-activated pDC reportedly differ in their ability to suppress autoaggressive T-cell responses, with the former being capable of differentiating IL-10-producing Treg cells [13] and the latter predominantly driving the development of cell contact-dependent Treg cells [8]. Collectively, a growing body of experimental evidence now indicates that DC maturation per se is neither a distinguishing feature of immunogenic as opposed to tolerogenic DC nor a control point for initiating immunity. It has also been proposed that cells of the mononuclear phagocyte system such as DC may exist along a continuum of activities from efficient antigen presenters to antigen-specific and nonspecific suppressors of T-cell activation [14]. This view implies that tolerogenic DC represent a regulated activity rather than a specific DC subset with specialized cell functions and supports the notion that tolerogenic DC are endowed with remarkable functional plasticity [15].
Alongside efforts to identify surface markers associated with DC tolerogenic activity, much attention has been devoted to the dissection of the mechanism(s) through which DC may promote tolerance. The phenotype of the DC subsets implicated in peripheral tolerance induction remains elusive, although the expression of signaling lymphocyte activation molecule, programmed cell death ligand-1, DEC-205 (CD205), and inhibitory receptors of the immunoglobulin-like transcript (ILT) family (ILT3/ILT4) has been detected on some tolerogenic DC populations [16], [17], [18], [19]. Recently, the expression of CCR9 has been assigned to pDC implicated in the suppression of graft-versus-host disease (GVHD) induced by allogeneic donor T cells in irradiated C57BL/6 recipient mice [20]. The main mechanisms underlying DC function in inducing peripheral tolerance include the promotion of Treg conversion from naive T cells and the expansion of pre-existing Treg cells, the release of IL-10 and other immunoregulatory cytokines, and the expression of indoleamine 2,3-dioxygenase (IDO) [9], [21], [22]. Activated Treg cells might, in turn, provide bioactive IFN-γ that promotes IDO expression in the APC compartment, thus establishing a positive feedback loop [23].
Section snippets
Cytokines as inducers of tolerogenic DC
DC, either at the immature or at the semimature stage, can differentiate both naturally occurring CD4+CD25+ Treg cells and adaptive, IL-10-secreting CD4+ type 1 (Tr1) cells either in vitro or in vivo [24], [25]. The phenotypic and functional features of the different Treg populations have been extensively detailed elsewhere [26], [27], [28], [29]. DC can be licensed to become tolerogenic by a variety of cytokines (Fig. 1). In mice, granulocyte–macrophage colony-stimulating factor (GM-CSF)
Expression of IDO and DC tolerogenicity
IDO, originally denoted D-tryptophan pyrrolase, is a single-chain oxidoreductase catalysing the degradation of L-tryptophan (Trp), the first step in the biosynthesis of nicotinamide adenine dinucleotide [46]. IDO transforms Trp to N-formylkynurenine, a product that is rapidly converted by formamidase to kynurenine, which in turn can either enter the bloodstream or undergo further metabolism to a series of molecules, collectively known as kynurenines (KYN). Suppressive Trp catabolites can exert
Rheumatoid arthritis
Rheumatoid arthritis (RA) is a predominantly Th1/Th17 skewed chronic inflammatory disease affecting peripheral joints. RA is characterized by a symmetrical polyarthritis of the synovial joints, leading to the destruction of cartilage and underlying bone. Inflammation is characterized by joint swelling, symmetric and often bilateral, that reflects hyperplasia of the synovial membrane and a cellular infiltrate made of monocytes/macrophages, T cells, B cells, plasma cells, mast cells, and DC [65].
DC-based therapeutic strategies for rheumatic disorders
Because DC play an undisputed role in inciting autoimmune diseases, the therapeutic harnessing of peripheral tolerance by tolerogenic DC represents an attractive avenue for clinical application. Animal models of autoimmunity have provided convincing evidence and solid proof of principle in favor of therapeutic benefits of cytokine-modulated tolerogenic DC. Theoretically, peripheral tolerance can be achieved either after in vitro exposure of DC preparations to cytokine stimuli with subsequent
Conclusions and future perspectives
An important issue to consider when designing DC-based immunotherapy protocols is whether tolerogenic DC inadvertently receive in vivo maturation signals in an inflammatory microenvironment and incite unwanted T-cell responses as fully mature DC. The phenotype of tolerogenic DC preparations modulated with G-CSF, IL-21, VIP, or low-dose GM-CSF is stable, indicating that the DC might be resistant to in vivo maturation-inducing stimuli [12], [33], [38]. We have previously shown that the in vitro
Acknowledgments
The studies reviewed herein were generously supported by the Stem Cell Project of Fondazione Roma, Rome, and by the Italian Ministry of Health.
References (210)
- et al.
Regulatory T cells and tolerogenic dendritic cells: from basic biology to clinical applications
Immunol Lett
(2004) Uncover the mystery of plasmacytoid dendritic cell precursors or type 1 interferon producing cells by serendipity
Hum Immunol
(2002)- et al.
Natural type I interferon-producing cells as a link between innate and adaptive immunity
Hum Immunol
(2002) - et al.
Human plasmacytoid-derived dendritic cells and the induction of T-regulatory cells
Hum Immunol
(2002) - et al.
Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity?
Trends Immunol
(2002) - et al.
Tolerogenic dendritic cells: cytokine modulation comes of age
Blood
(2006) - et al.
Different faces of regulatory DCs in homeostasis and immunity
Trends Immunol
(2005) - et al.
Induction of tolerogenic DCs: “you are what you eat.”
Trends Immunol
(2003) - et al.
Antigen-induced regulatory T cells
Blood
(2004) - et al.
Tr1 cells: from discovery to their clinical application
Semin Immunol
(2006)
Interferon-λ-treated dendritic cells specifically induce proliferation of FOXP3-expressing suppressor T cells
Blood
High expression of ILT3 and ILT4 is a general feature of tolerogenic dendritic cells
Transpl Immunol
Role for granulocyte colony-stimulating factor in the generation of human T regulatory type 1 cells
Blood
Granulocyte-colony stimulating factor mobilizes T helper 2-inducing dendritic cells
Blood
G-CSF mobilizes slanDCs (6-sulfo LacNAc+ dendritic cells) with a high proinflammatory capacity
Blood
Hepatocyte growth factor favors monocyte differentiation into regulatory interleukin (IL)-10++IL-12low/neg accessory cells with dendritic-cell features
Blood
GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase
Immunity
Toward the identification of a tolerogenic signature in IDO-competent dendritic cells
Blood
Regulation of human auto- and alloreactive T cells by indoleamine 2,3-dioxygenase (IDO)-producing dendritic cells: too much ado about IDO?
Blood
A two-step induction of indoleamine 2,3 dioxygenase (IDO) activity during dendritic-cell maturation
Blood
Lipid and protein oxidation contribute to a prothrombotic state in patients with type 2 diabetes mellitus
J Thromb Haemost
Rheumatoid arthritis synovium contains two subsets of CD83-DC-LAMP-dendritic cells with distinct cytokine profiles
Am J Pathol
Type I Interferon controls the onset and severity of autoimmune manifestations in lpr mice
J Autoimmun
Interferon and granulopoiesis signatures in systemic lupus erythematosus blood
J Exp Med
Plasmacytoid dendritic cells in immunity
Nat Immunol
Reciprocal control of T helper cell and dendritic cell differentiation
Science
The enigmatic plasmacytoid T cells develop into dendritic cells with interleukin (IL)-3 and CD40-ligand
J Exp Med
Tolerogenic dendritic cells
Annu Rev Immunol
Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance
Proc Natl Acad Sci USA
The induction of tolerance by dendritic cells that have captured apoptotic cells
J Exp Med
Induction of interleukin 10-producing, nonproliferating CD4+ T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells
J Exp Med
Macrophages as APC and the dendritic cell myth
J Immunol
A novel inhibitory receptor (ILT3) expressed on monocytes, macrophages, and dendritic cells involved in antigen processing
J Exp Med
Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4
Nat Immunol
CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease
Nat Immunol
Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase
Science
CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function
J Exp Med
Modulation of tryptophan catabolism by regulatory T cells
Nat Immunol
CD4+CD25+ suppressor T cells: more questions than answers
Nat Rev Immunol
The regulatory T cell family: distinct subsets and their interrelations
J Immunol
Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25)Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases
J Immunol
The Janus face of CD4+CD25+ regulatory T cells in cancer and autoimmunity
Curr Med Chem
Granulocyte–macrophage colony-stimulating factor prevents diabetes development in NOD mice by inducing tolerogenic dendritic cells that sustain the suppressive function of CD4+CD25+ regulatory T cells
J Immunol
Cutting edge: in vitro-generated tolerogenic APC induce CD8+ T regulatory cells that can suppress ongoing experimental autoimmune encephalomyelitis
J Immunol
Tolerogenic semimature dendritic cells suppress experimental autoimmune thyroiditis by activation of thyroglobulin-specific CD4+CD25+ T cells
J Immunol
Vasoactive intestinal peptide induces regulatory dendritic cells with therapeutic effects on autoimmune disorders
Proc Natl Acad Sci USA
Are interleukin-16 and thrombopoietin new tools for the in vitro generation of dendritic cells?
Blood
IL-10 prevents the differentiation of monocytes to dendritic cells but promotes their maturation to macrophages
Eur J Immunol
Macrophage colony-stimulating factor drives cord blood monocyte differentiation into IL-10highIL-12absent dendritic cells with tolerogenic potential
J Immunol
Granulocyte colony-stimulating factor promotes the generation of regulatory DC through induction of IL-10 and IFN-α
Eur J Immunol
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