Review articleRegulatory dendritic cells in autoimmunity: A comprehensive review
Introduction
Dendritic cells (DCs) were first described by Prof. Ralph Steinmann in the 1970s [1], [2] as being a distinct hematopoietic lineage with unusual morphology, movement and potent capacity of stimulating primary mixed leukocyte reaction. Prof. Ralph Steinmann was awarded the 2011 Nobel Prize in Physiology or Medicine for his contribution in discovering DCs and defining the role of DCs in adaptive immunity. Since the discovery of DCs, our knowledge about the functional properties of DCs, the role of DCs in the pathogenesis of infections, transplantation, allergy, autoimmunity, and application of DC vaccine in cancer treatment has greatly expanded.
It is now recognized that DCs represent a complicated heterogeneous population of leukocytes with distinct developmental origins, phenotype markers and immunological functions. Distributed throughout nearly all the lymphoid and non-lymphoid organs, DCs could sense a wide range of ‘danger signals’ both from invading microbial and from injured host cells through pattern recognition receptors (PRRs) [3], [4]. During maturation, DCs weaken their capacity of uptaking and processing antigen and meanwhile become progressively powerful in presenting antigen to naïve T cells. Activated DCs upregulate the expression of MHC molecules, co-stimulatory molecules and proinflammatory cytokines to prime T cell proliferation and differentiation and thus initiate the activation of adaptive immune response. Conversely, DCs play an important role in the development of both central tolerance and periphery tolerance through a complicated immune network [5]. DCs, under specific physiological or pathological conditions, may express anti-inflammatory cytokines and inhibitory receptors and thus promote tolerogenic immune responses. A variety of environmental stimuli have been shown to direct DCs to suppress immune responses through the generation of anergic and regulatory T cells and altering the quality of T cell activation and differentiation. Besides, many intrinsic molecules have been found to regulate DCs maturation or activation thus contributing to control of autoimmunity.
Immunological tolerance is classified into two processes, central tolerance and peripheral tolerance. Central tolerance takes places in thymus and bone marrow where most of the auto-reactive lymphocyte clones are eliminated at an immature stage. Peripheral tolerance involves distinct mechanisms that suppress the activation of auto-reactive T cells and B cells that enter the periphery [6]. Autoimmunity refers to the specific immune response towards self-components when the immunological tolerance checkpoints failed. Unresolved autoimmune responses can even cause tissue damage and organ malfunction, which are now categorized as distinct types of autoimmune diseases (AID) classified either systemic (e.g. systemic lupus erythematosus (SLE), rheumatoid arthritis (RA)) or organ specific (e.g. type 1 diabetes (T1D)) [7]. Considering the critical role of DCs in inducing adaptive immunity and maintaining immune tolerance, much attention has been paid to the bidirectional role of DCs in either inciting or preventing autoimmune diseases. In this Review, we will discuss the phenotypic and functional properties of regulatory DC, with special focus on the characteristic of regulatory DCs that is induced either by physiological or pathological stimulation. The cell intrinsic mechanisms for the maintenance of DC tolerance are also described. Finally, we will discuss the complex role of DCs in the process of autoimmunity and autoimmune diseases, and the potential application of regulatory DCs for treatment of autoimmune diseases both in human and in mouse models.
Section snippets
DC maturation and activation
As professional APC, DCs play an essential role in bridging the innate and adaptive immune systems [8]. Immature DCs typically express low levels of MHC II and costimulatory molecules and therefore incline to promote T cell anergy and Treg cell generation, which is important for the maintenance of immune homeostasis [9], [10], [11], [12], [13]. Meanwhile, immature DCs express high levels of pattern recognition receptors (PRRs) (such as Toll-like receptors (TLRs), retinoic-acid-inducible gene I
Regulatory DCs: generation and function
Growing evidence suggests different DC subsets, either naturally arising or experimentally induced, play critical roles in the maintenance of immune homeostasis via induction of immune tolerance and regulation. The regulatory capacity of DCs depends on their immature state and can be induced by immunosuppressive mediators, genetic manipulation, certain pathogenic stimuli, signals from immune cells or apoptotic cells, and tissue or tumor microenvironment [53](Fig. 1). Regulatory DCs (DCreg)
Endogenous regulation of DC tolerance
Though a variety of extrinsic factors such as immune suppressive factors and apoptotic cells could program DCs to a tolerogenic state, the immune environment is a dynamic, flexible and complicated network full of endogenous and exogenous components and therefore could hardly present only tolerogenic signals to DCs. In this regard, it's more interesting to look into the endogenous regulatory mechanisms for DC tolerance. Indeed, the tolerogenic potential of DC is intrinsically antagonized or
Bi-directional roles of DC in autoimmunity
In line with the multifaceted role of DCs in inducing adaptive immune responses and immune tolerance, DCs have played both activating and inhibitory roles in autoimmune responses [130]. Ablation of DCs in mice caused spontaneous development of autoimmune disease under steady-state conditions, indicating a critical role of DCs in preventing autoimmunity and maintaining immune tolerance, as we have discussed above [131]. However, DCs also play key roles in driving autoimmunity via various
Conclusions and future directions
As the most powerful APC, DCs serve as the key bridge between innate and adaptive immunity. DCs also function as a critical switcher between immune activation and immune tolerance. As discussed above, regulatory DCs refer to a heterogeneous DCs population with regulatory function, which include immature DCs at steady state, or distinct DC subsets under infectious condition or following artificial treatment. Further investigation is required to address the origin, development, and genetic
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