Despite similar basic function of antigen presentation, DCs differ in their developmental pathways, location, migratory properties, phenotypic markers and immunological functions. Thus, DCs are heterogeneous and several subtypes with distinct features have been identified in lymphoid and non-lymphoid tissues of human and mouse [1,3]. The major subtypes of human DCs are Langerhans cells, interstitial dermal DCs, monocyte-derived inflammatory DCs (Mo-DCs), BDCA-1⁺ and BDCA-3⁺ myeloid DC subsets, and plasmacytoid DCs (pDCs). The major subsets of mouse DCs include CD4^-CD8α^hiCD205^hiCD11b^- DCs, CD4⁺CD8α^-CD205^-CD11b⁺ DCs, CD4^-CD8α^-CD205^-CD11b⁺ DCs, CD4^-CD8α^-CD205⁺CD11b^- DCs, plasmacytoid DCs, and Langerhans DCs [3]. However, as depicted in Table 1, human and mouse DC subsets vary in their expression of CD markers (Table 1) [4].

Table 1

Differentiation Markers on Different Subsets of DCs in Human and Mice

Phenotypically, DCs are identified in “immature” and “mature” stage, based on the expression of surface markers [2]. Resting or immature DCs have high capacity to capture and internalize antigens due to surface expression of receptors that enables the recognition and endocytosis of potential antigens. These receptors include members of pattern recognition receptors (PRRs) family (such as Toll-like receptors (TLRs), C-type lectin receptors (CLRs), intracytoplasmic nucleotide oligomerization domain (NOD)-like receptors (NLRs)), Fc receptors (FcR), complement receptors, scavenger receptors and receptors involved in uptake of apoptotic bodies such as phosphatidylserine receptor. The expression of surface receptors differs with DC subsets and hence enables identification of subtypes [4]. DCs also possess numerous cytokine receptors that enable them to respond to the appropriate stimuli. Thus, immature DCs act as immunological sensors that receive stimuli from environment to alert the immune system. However, immature DCs are poor stimulators of T cells and must undergo a maturation and activation process.

Upon antigen capture by immature DCs, a complex process of maturation and activation is initiated based on the nature of the stimuli. The molecules that provide maturation-associated signals include pathogen-derived molecules (eg., dsRNA, LPS, CpG), dying cell components, tissue factors such as hyaluronan fragments, heparin sulphate, immune complexes and inflammatory cytokines [5]. The components of the dying cells include heat shock proteins (HSPs), high-mobility group box1 proteins (HMGB1), β-defensins, ATP and uric acid, which are collectively called damage-associated molecular pattern molecules (DAMPS) [6]. NF-κB and mitogen-activated protein kinase are the two major signaling pathways that are activated by these stimuli during maturation of DCs [7,8].

Maturation is defined as the series of phenotypic changes that enables DCs to initiate immunity as professional APCs [9]. This process involves similar morphological and functional changes in both human and mouse DCs [9] that include (i) loss of endocytic/phagocytic receptors; (ii) morphological changes such as the loss of adhesive structures, cytoskeleton reorganization, and the acquisition of high cellular motility; (iii) secretion of immunoregulatory cytokines and chemokines such as IL-1β, IL-6, IL-10, IL-12, IL-23, TNF, CCL17, CCL19 and CCL22; (iv) up-regulation of co-stimulatory and adhesion molecules CD80, CD86, CD40, CD54, CD58 critical in mediating clustering with and activation of T cells; (v) translocation of MHC class I/II compartments to the cell surface; and (vi) migration of mature DCs into regional/draining lymphoid tissue. As a result, antigen acquired in peripheral sites is retained, processed and presented to T cells in lymph nodes.

The process of T-cell activation is regulated primarily by signaling events derived from the T-cell receptor TCR (signal 1) and from co-stimulatory and adhesion molecules (signal 2) CD80, CD86, CD40, CD54, CD58 on APCs and CD28, CD154, CD11a and CD2 on T cells. The CD80 and/or CD86–CD28 interactions provide signals important for T-cell activation and survival. CD40–CD154 interactions are crucial for the development of CD4⁺ T-dependent effector functions such as help for B-cell differentiation and class switch. The interactions of adhesion molecules CD54 and CD11a, and CD58 and CD2 play a central part in the clustering of DCs and CD4⁺ T lymphocytes and facilitate TCR triggering by increasing T-cell–DC interactions at low antigen densities. An additional signal has also been proposed in the form of immunomodulatory cytokines (signal 3) produced by activated DCs that dictate the polarization of CD4⁺ T cells towards Th1, Th2, Th17 or regulatory T cells (Tregs) (Fig. 1) [10]. Interleukin (IL)-12 has an important role in the differentiation of Th1 cells, and IL-4 is crucial for Th2 differentiation. IL-1β and IL-6 promote IL-17 and IL-21 production from activated and memory human T cells. IL-21 promotes the differentiation of human Th17 cells from naïve CD4+ T cells in the presence of transforming growth factor (TGF)-β, whereas IL-23 might further expand or stabilize differentiated Th17 cells [11-14].

Fig. (1) (a) Immature DCs present with high capacity to take up exogenous antigens. The recognition of antigen-associated PAMPs by PRRs (signal 0) leads to maturation and activation of DCs. In endosomes/lysosmes, the internalized antigens are processed into smaller peptides. These antigenic peptides bind to MHC II molecules and transported to cell surface. EPR, endoplasmic reticulum (b) The ‘antigen-educated’ DCs present antigenic peptides in the context of MHC II to TCR of naïve CD4+T cells (Signal 1). These mature and activated DCs express high levels of MHC, co-stimulatory (CD40, CD80 and CD86) and adhesion molecules (CD54 and CD58) (signal 2) and secrete high amounts of cytokines IL-1α, IL-6, IL-10, IL-12, IL-23 and TNF (Signal 3) that play a critical role in inflammation and differentiation of CD4+T cells. (c) The interaction of signaling molecules at APC-T cell interface (d) CD4+T cells under the influence of signaling by DCs and DC-derived cytokines can be differentiated into 4 distinct subclasses expressing distinct transcription factors: Th1, Th2, Th17 and induced Tregs (iTregs). The figure is reprinted from Trends Pharmacol Sci 2009, 30:287-295 (ref. [10]) with permission from Elsevier.

In addition to T cell stimulation, DCs contribute to the stimulation of B cells, both in the lymph node T cell areas and in germinal centers. Antigens in the immune complex captured by inhibitory Fc receptor (FcRγIIB) can be retained in non-degradative intracellular vesicles and presented in native form to B cells [15]. DCs can also modulate the functions of non-specific effectors such as natural killer cells and natural killer T cells and influence the outcome of immune response [16, 17].

In addition to their central role in initiating adaptive immunity, DCs are also involved in the induction of immune tolerance in both central and peripheral compartments by different regulatory mechanisms that include, clonal deletion, clonal anergy, receptor editing of T/B cells and generation of Tregs [16, 17]. Role of DCs in generation of regulatory T cells is of prime importance [15]. In human thymus, the thymic stromal lymhopoietin (TSLP) derived from the hassall’s corpuscles instruct DCs to switch from negative selection of autoreactive T cells to positive selection of natural Tregs (nTregs). Interestingly, the preformed immature myeloid tolerogenic DCs carrying peripheral antigens migrate into the thymus and induce the generation of nTregs in vivo [15]. In addition, immature/tolerogenic DCs or DCs stimulated to produce IL-10/ TGF-β induce Tregs in peripheral tissues referred to as induced regulatory cells (iTregs) [18, 19]. Tregs play a crucial role in maintaining immune tolerance by acting on several cellular targets [20, 21].

Autoimmunity refers to inappropriate immune response against self-components of the host that might result in pathological conditions. A low level of autoreactivity is acknowledged as physiologic and crucial for normal immune function [22]. Autoimmune diseases are clinical syndromes that occur in selected genetic backgrounds characterised by the abnormal activation of T cells, B cells or both in the absence of on going infection or other discernible cause [23]. Autoimmune diseases affect approximately 5% of the population based on genetic characters and environmental factors. They can be clinically classified either systemic (eg., systemic lupus erythematosus (SLE) or organ specific (eg., type 1 diabetes mellitus) [23].

A breakdown in immune tolerance is central to the initiation and progression of an autoimmune disease. Given the central role in induction of immune response and tolerance, DCs are the most sought after cells in inciting autoimmunity and its sustenance to autoimmune diseases [18, 24-28]. In human leukocyte antigen-restricted autoimmune diseases, DC priming of the immune response in lymphoid organs is a requisite first step that leads to the activation of T cells and the production of pathogenic autoantibodies and the ensuing chronic inflammatory process [29-31]. Individuals with autoimmune disease show a high number of aberrantly activated DCs either in circulation or in the autoimmune lesions secreting large amounts of proinflammatory cytokines that mediate inflammation and differentiation of pathogenic Th1 and Th17 cells [26]. In the mouse model, altered DC homeostasis has been demonstrated to result in an apparent autoimmune response, thus signifying a central role of DCs in maintaining immune self-tolerance and potential to incite autoimmunity [32, 33]. Further, defects in the apoptosis of the immune cells and defective clearance of apoptotic cell debris due to an impaired uptake can result in development of autoimmunity. The priming of autoreactive lymphocytes by activated DCs that have taken up apoptotic materials may lead to break down of self-tolerance [34]. The role of TLRs expressed on different DC subsets has been increasingly evidenced in the pathogenesis of many autoimmune diseases [35, 36]. An important sequel of continued antigenic stimulation via DCs is the formation of lymphoid structures at the site of inflammation. By coordinating the recruitment and/or activation of other immune cells, DCs can drive the generation of ectopic lymphoid tissues, as in the case of inflamed synovia in rheumatoid arthritis (RA) and SLE [18, 19].

Although Tregs can suppress the maturation and activation and the production of inflammatory cytokines by recently activated DCs (Fig. 2) [31, 37-40], chronically activated DCs can escape suppression by Tregs and generate activated T cells that are refractory to the suppression by Tregs. High amounts of pro-inflammatory cytokines that are released by DCs due to constant and prolonged activation can render Tregs functionally defective. For example, prolonged exposure to TNF can inhibit the expression of FoxP3 and the function of Tregs by signaling through TNF receptor II [41]. Further, IL-6, IL-12, and IL-1β may also promote autoimmunity by interfering with the regulatory functions of Tregs and promoting activation and expansion of effector T cells [31]. In addition to directly suppressing the functions of Tregs, DC-derived cytokines such as IL-6, IL-1β, and IL-23 can reciprocally regulate the populations of iTregs and IL-17-producing pathogenic Th17 cells [42].

Fig. (2) Several mutually nonexclusive mechanisms have been proposed to account for the modulation of DCs by Tregs. The suppression of DCs by Tregs is mediated by both soluble factors and cell-associated molecules. However, recent reports suggest that CTLA-4 molecule has a key role in Treg-mediated suppressive functions. (a) Treg-derived IL-10 and TGF-β induce a suppressive phenotype in DCs and inhibit inflammatory cytokine expression by DCs while enhancing the secretion of the anti-inflammatory cytokine IL-10. (b) Activated Tregs express high levels of granzyme A and perforin and exert CD18/CD54 adhesive interaction-dependent cytotoxicity against both immature and mature DCs, thus reducing the antigen-presenting and co-stimulatory pool. (c) CTLA-4 interaction with B7 molecules transduces a negative signal for DCs CTLA-4 diminishes the co-stimulatory molecules CD80 and CD86 and converts DCs into less potent APCs with reduced T cell stimulatory potential. CTLA-4 can also induce indoleamine 2,3-dioxygenase (IDO) expression in DCs. IDO catalyzes the conversion of tryptophan into kynurenines, which are potent immunosuppressive metabolites. (d) Tregs can interact with MHC class II on DCs via lymphocyte activation gene-3 (LAG-3), a CD4-related transmembrane protein that inhibits DC activation by a mechanism involving ERK-mediated recruitment of SHP-1. (e) Tregs express CD39 (nucleoside triphosphate diphosphohydrolase-1), an ectoenzyme that degrades ATP to AMP. Thus, Tregs reduce ATP-mediated activation of DCs and the adjuvant activities of ATP. Some of these mechanisms are also reported to be critical in Treg-mediated regulation of functions of macrophages and B cells. The figure is reprinted from Am J Pathol 2009, 174:1575-1587 (Ref. [31]) with permission from the American Society for Investigative Pathology.

Type 1 interferons (IFN-α and IFN-β) are secreted in large amount by pDCs not only following viral infection, but also in autoimmune diseases [1]. In psoriasis, pDCs accumulate in the inflamed skin at an early stage of the disease, and these cells secrete type I IFN [43]. In insulin-dependent diabetes mellitus, elevated expression of IFN was found in the pancreas of recently diagnosed patients, though the role of pDCs is unclear [44]. In idiopathic inflammatory myopathies, DCs present in inclusion body myositis and polymyositis are primarily myeloid DCs, whereas in dermatomyositis, type I IFN producing pDCs have been found abundantly in muscle tissue [45]. In Sjogren’s syndrome, an autoimmune disease affecting mainly salivary and lacrimal glands, pDCs infiltrate salivary glands, where IFN-inducible genes are over-expressed [46]. In immune thrombocytopenic pupura patients, DCs are found to be highly efficient in presenting apoptotic platelets and stimulating autologous T-cell proliferation [47].

DCs are the prime initiators and mediators of autoimmune diseases in an altered host microenvironment (cytokine imbalance) arising out of environmental and genetic perturbations. DCs act in concert with adaptive and other innate immune cells in moulding the autoimmune response. The emerging knowledge of the importance of DCs, DC-derived cytokines, and intracellular signal transduction pathways in mediating and creating an inflammatory environment in autoimmune diseases provides a rationale for pursuing strategies to block these inflammatory pathways for the therapeutic purposes.