Dendritic cells in the regulation of immunity and inflammation

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Review

Dendritic cells in the regulation of immunity and inflammation ⁎

Cheng Qiana, , Xuetao Caoa,b,

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a

National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China b

A R T I C L E I N F O

A B S T R A C T

Keywords: Dendritic cells Immune regulation Innate immunity Inflammation

As potent antigen-presenting cells, dendritic cells (DCs) comprise the most heterogeneous cell population with significant cellular phenotypic and functional plasticity. They form a sentinel network to modulate immune responses, since intrinsic cellular mechanisms and complex external, environmental signals endow DCs with the distinct capacity to induce protective immunity or tolerance to self. Interactions between DCs and other cells of the immune system mediate this response. This interactive response depends on DC maturation status and subtype, as well as the microenvironment of the tissue location and DC-intrinsic regulators. Dysregulated DCs can initiate and perpetuate various immune disorders, which creates attractive therapeutic targets. In this review, we provide a detailed outlook on DC ontogeny and functional specialization. We highlight recent advances on the regulatory role that DCs play in immune responses, the putative molecular regulators that control DC functional responding and the contribution of DCs to inflammatory disease physiopathology.

1. Introduction Dendritic cells (DCs) are specific antigen-presenting cells that function as messengers between innate and adaptive immune responses. DCs are very few in number, but they have a ubiquitous distribution in the body to serve as sentinels for foreign and dangerous material [1]. Immune system activation in response to pathogens or sterile inflammation involving both innate and adaptive immunity is a double-edged sword [2]. Full activation of an inflammatory response is essential for the initial host defense, particularly against most infections; however, inappropriate activation or overactivation of inflammatory responses may elicit damaging inflammation to the host [3]. A proper response to maintain immune homeostasis occurs through a precise, complex network of regulatory mechanisms [4]. So, DCs emerge as key players for the immune system. Research efforts continually refine our knowledge on DC functions to initiate both protective pro-inflammatory and tolerogenic immune responses [5]. Typically, DCs recognize a wide range of ‘danger signals’ both from invading microbes and injured host cells through binding either pathogen-associated molecular patterns (PAMPs) or damage-associated molecular pattern molecules (DAMPs) to specialized pattern recognition receptors (PRRs) [6]. Antigen recognition by DCs induces phagocytic processing of antigens and antigen presentation, increases expression of costimulatory molecules and cytokine production, and ultimately primes naïve T cells to activate adaptive immunity [7]. DCs

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can also regulate immune responses by generating both central and peripheral tolerance and controlling inflammatory responses by various mechanisms, such as inducing apoptosis of autoreactive T cells and T cell anergy, expanding regulatory T cells and limiting other effector cell responses [8]. Through interactions with other immune system cells accompanied by cytokine release or cell–cell contact, DC subsets with significant phenotypic and functional plasticity perform these complicated tasks. Recent efforts to characterize the regulators that program the function of DCs suggest that complex environmental signals and intrinsic cellular mechanisms direct DC functions [9]. Since alterations in DC biology underlie various inflammatory immune disorders[10], understanding how different subsets of DCs regulate immunity and inflammation is vital to develop new intervention strategies to target the immune system in various pathologies. In this review, we summarize the current knowledge about the differentiation and functional classification of DCs. We highlight recent advances on DC biology through extrinsic regulators from the local tissue microenvironment, such as cell–cell contact, soluble mediators, and intrinsic regulators, like membrane-associated receptors, intracellular enzymes and epigenetic factors. We also describe the dual role of DCs in the pathogenesis of inflammatory diseases and immunomodulatory strategies used in therapeutic interventions.

Corresponding authors at: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China E-mail addresses: [email protected] (C. Qian), [email protected] (X. Cao).

https://doi.org/10.1016/j.smim.2017.12.002 Received 11 August 2017; Accepted 8 December 2017 1044-5323/ © 2017 Elsevier Ltd. All rights reserved.

Please cite this article as: Qian, C., Seminars in Immunology (2017), https://doi.org/10.1016/j.smim.2017.12.002

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2. Differentiation and functional classification of DCs

coordinated and complex process of DC maturation. However, recent studies revealed new insights into the ontogeny and development of a third DC population, so-called “inflammatory DCs”, which only form in response to inflammatory stimuli, not at steady state [24]. Most inflammatory DCs share common features with cDCs, such as morphology, phenotype, migratory properties and ability to activate CD4+ and CD8+ T cells. However, they differ in their lineage of origin [25]. cDCs can be modeled in vitro by monocytes in the presence of IL-4 and GM-CSF, while inflammatory DCs develop from bone marrow-derived DCs cultured with GM-CSF in vitro [26]. Inflammatory DCs may initially derive from Ly6Chi monocytes, which emigrate from the bone marrow depending on CCR2 and travel to inflamed/infected tissues to fully differentiate at the site of inflammation [27,28]. Under different inflammatory conditions, early hematopoietic precursors such as HSCs, CLP and CDPs were also identified as the direct precursors of inflammatory DCs to bypass normal lineage commitment steps [29]. These inflammatory DCs, which produce TNF-α and nitric oxide (NO), play a major role to clear infectious agents, such as Listeria monocytogenes, Brucella melitensis, Leishmania major and Trypanosoma brucei [30,31]. It is interesting that a myeloid population accumulating within the tumor after adoptive cell therapy is phenotypically similar to inducible NO synthase- and TNF-producing inflammatory DCs, which is important for adoptively transferred CD8+ cytotoxic T cells to destroy tumors, providing a rationale for switching the balance between proand anti-tumor myeloid cells in the tumor microenvironmen [32]. Inflammatory DCs then migrate to lymphoid nodes and present antigens to naive CD4+ T cells to induce TH1 [33,34], TH2 [35,36] or TH17 [37] cell differentiation depending on the inflammatory environment. Human inflammatory DCs are found in two different inflammatory environments, ascites from untreated ovary and breast cancer patients and synovial fluid from RA patients, which are derived from monocytes and are involved in the induction and maintenance of Th17 cell responses through the release of Th17 cell-polarizing cytokines [38]. So, inflammatory DCs appear not only during pathogenic inflammation, but also in experimental models of inflammatory diseases like asthma [39] and psoriasis [40], rheumatoid arthritis patients and cancer patients. This prevalence and pattern suggests inflammatory DCs are an important target for optimal vaccine design [41].

2.1. Ontogeny of DCs Traditionally, DCs arise from hematopoietic stem cells (HSCs). DC differentiation from HSCs is a multistep process that varies spatiotemporally [11]. In bone marrow, CD34+ HSCs can generate multipotent progenitors (MPPs), which can then differentiate into common myeloid progenitors (CMPs) and common lymphoid progenitors (CLPs). Adoptive transfer of CMPs and CLPs populations into irradiated animals revealed that these early precursors have almost similar efficiency to produce conventional DCs (cDCs) and plasmacytoid DCs (pDCs) in mice. An analogous potential can occur in human CMPs and CLPs cultured in vitro. However, the ability of CMPs or CLPs to differentiate into these two major categories of DCs is confined to only those subsets expressing fms-related tyrosine kinase 3 (Flt3). Flt3+ CMPs differentiate into macrophage-DC progenitors (MDPs), the common precursor for monocytes, macrophages and DCs. Common DC progenitors (CDPs) are derived from MDPs and produce a DC-restricted progenitor that exclusively generates a precursor DC population (pre-DCs) but not monocytes or macrophages. The terminal differentiation of cDCs from a cascade of bone marrow DC-committed precursors occurs locally in lymphoid organs and peripheral tissues throughout the body [12]. Compared to cDCs, pDCs can rapidly secrete significant type I IFN quantities in response to foreign nucleic acids [13]. The ontogeny of pDC differs significantly from cDCs. pDCs develop from a continuum of Flt3+ c-Kitlow progenitors, including CLPs and CDPs, and fully develop in the bone marrow [14]. Transcription factor E2-2 is an essential and specific regulator of pDC development [15]. Following development in the bone marrow, pDCs circulate in the blood and then enter peripheral and lymphoid tissues. At steady state, mouse cDCs are broadly divided into two classes: lymphoid DCs and migratory DCs [16]. Lymphoid DCs, encompassing subclasses CD8α+ and CD11b+ DCs, reside mainly in spleen and tissuedraining lymph nodes and rapidly take up antigens from the bloodstream and lymph for T cells presentation. Migratory DCs can further separate into CD103+ and CD11b+ cDCs, which traffic from peripheral tissues, such as skin, lung, liver, kidney and intestinal tract, to draining lymph nodes charged with tissue antigens [17]. Transcription factors, Batf3 and IRF-4, control cDC differentiation into CD8α+/CD103+ and CD11b+, respectively [18]. Recently, studies made significant progress to elucidate mouse DC development. Much less is known about the ontogeny of human DCs, because of the scarcity in blood and the difficulties to isolate them from other human tissues. Most of our knowledge about human DC biology comes from experiments using cells derived in vitro from monocytes or from CD34+ hematopoietic progenitors [19]. However, recent studies show that steady-state human blood and secondary lymphoid organs contain at least three DC subsets [20]: CD141+ myeloid DCs, CD1c+ myeloid DCs and pDCs, which differ considerably from monocyte- and CD34+-derived DCs in vitro. Classification of DC subset functional homology across species shows that CD141+ myeloid DCs (also known as thrombomodulin+ or BDCA3+) and CD1c+ myeloid DCs (also known as BDCA1+) are homologous to mouse lymphoid CD8+ and CD8− DC subsets, respectively [21]. Only human pDCs express typical pDC markers like CD123 and BDCA2, while murine pDCs uniquely express BST2 and Siglec H [22].

2.3. Regulatory DCs DCs are critical to regulate the subtle balance between immunity and tolerance [42]. Aside from their unique capacity to present antigens and prime T-cell responses, DCs may have an important immuneregulatory function essential for both central and peripheral tolerance [43]. Growing evidence suggests regulatory DCs can contribute to immunological tolerance by inhibiting T cell responses, inducing T cell unresponsiveness and apoptosis and generating regulatory T (Treg) cells [44]. Thymic DCs are generally classified into three subtypes: resident CD8α+ SIRPα− cDCs, migratory CD8α−CD11b+SIRPα+ cDCs and CD11cintCD45RAint pDCs [45]. All three thymic DC subsets can mediate central tolerance through different mechanisms [46]. Recent cell lineage tracing studies using fluorescent reporter mice show that intrathymic precursors of thymic resident cDCs develop intrathymically from thymic-homing, bone marrow progenitors via CCR7- and CCR9mediated chemokine signals [47]. Although thymic resident cDCs comprise the most abundant thymic DC subset, they do not have efficient exchange with circulating peripheral DCs and the chemokine XCL1 produced predominantly by medullary thymic epithelial cells mediates medullary accumulation of thymic dendritic cells that express the chemokine receptor XCR1 [48]. They can provide immature T cells with a distinct self-antigenic repertoire and cross-present both bloodderived and tissue-specific antigens from medullary thymic epithelial cells to educate thymocytes. As shown in parabiosis experiments, thymic migratory DCs arrive from the peripheral circulation, where

2.2. Inflammatory DCs pDCs and cDCs arise via pre-DCs, which exit the bone marrow and travel through the blood stream to lymphoid and non-lymphoid tissues under steady state and inflammatory conditions (Fig. 1). Different subtypes of immature DCs either populate the skin, mucosal surfaces and most solid organs or circulate in the blood to act as sentinels for PAMPs and DAMPs [23]. This activation by “danger signals” induces a 2

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Fig. 1. A simplified view of the origin, distribution and migration of murine DC subsets under steady state and inflammatory conditions. In bone marrow, CD34+ hematopoietic stem cells (HSCs) give rise to common myeloid progenitors (CMPs) or common lymphoid progenitors (CLPs) via multipotent progenitors (MPPs). Flt3+ CMPs differentiate into granulocyte and macrophage DC progenitors (MDP), which then give rise to monocytes and common DC progenitors (CDP). CDPs in turn differentiate to conventional DC precursors (pre-cDCs) and plasmacytoid DCs precursors (pre-pDCs). The pre-pDCs can also differentiate from Flt3+ CLPs and give rise to mature pDC in bone marrow. MDPs can differentiate into monocytes expressing high levels of the Ly6C marker in bone marrow. Pre-cDCs, Ly6Chi monocytes and pDC travel via the blood to peripheral organs, where they can change their phenotype and function depending on environmental cues. Inflammatory DCs differentiate separately from Ly6Chi monocytes only during inflammation. Once there, pre-cDCs undergo a final differentiation stage that generates CD103+ and CD11b+ migratory DCs in tissues and CD8α+ and CD11b+ lymphoid DCs in lymphoid organs.

3. Regulation of DCs function

CCR2/α4 integrins may localize the DCs to the cortex and the perivascular regions of the thymus [49]. Thymic pDCs are recruited from the blood to the corticomedullary region of the thymus through a CCR9 dependent process [50]. Unlike thymic resident DCs that present a wide array of self-antigens, thymic migratory DCs and pDCs specialize in presenting systemic blood-borne antigens and innocuous peripheral antigens, respectively, and contribute to clonal deletion and natural Treg-cell induction [51,52]. In the periphery, functional DC subsets with various locations and roles participate in peripheral tolerance [53]. At steady-state, tissueresident immature DCs normally express low levels of DC maturation markers (CD40, CD80, CD86 and MHCII, etc.) and lack proinflammatory cytokine production (IL-12, IL-1β and IL-6,etc.) [54]. Steady state migratory DCs acquire antigens in non-inflamed tissues and carry these antigens to the draining lymph organs where they favor the differentiation of T cell subsets with regulatory properties rather than inducing effector cells [44]. For example, CD103+ DCs in intestinal mucosa can uptake dying cells and cross-present cell-associated antigens to induce Foxp3+ Treg cells [55–57]. Further, up-regulation of DC inhibitory membrane receptors, such as PD-L1 [58,59], ILT4 [60], CTLA-4 [61] and FasL [62], can promote tolerance, because functional anergy or cell death can modulate T effector cells during activation. Regulatory DCs can also secrete a high levels of anti-inflammatory cytokines, such as IL-10 and TGF-β, which are crucial to impair NK and T cell activation and stimulate Treg cell differentiation and expansion in several models [63,64]. Recent studies propose that regulatory DCs promote regulatory B (Breg) cell generation, who suppress pro-inflammatory T cell differentiation and induce Treg cells by producing anti-inflammatory cytokines and initiating contact-mediated mechanisms [65]. Qian et al. described that DC-derived IFN-β and CD40L can induce the differentiation of CD19hiFcγRIIbhi Breg subsets, which secrete IL-10, exert phagocytic capacity and perform regulatory functions [66].

Recent evidence indicates that DCs oscillate between immune activation and tolerance. Although the immature state of DCs influences their function, numerous regulators fine tune DC function. Our discussion here will focus on cross-talk between DCs and other cells from local microenvironment, soluble factors and intrinsic regulators, whose presence directly relates to DC function (see Fig. 2 for a general overview). 3.1. Multiple cross-talks between DCs and other cells from local microenvironment DCs localize in close proximity to other immune cells, such as T cell, B cells, NKT cells and all granulocyte subtypes, which potentially influence DC immunomodulatory capacities [67]. The accepted view is that mature DCs prime the T cell response, even though DCs receive signals from T cells that trigger DC apoptosis to downregulate immune responses. As described above, DCs can induce Treg cell generation, and, conversely, Treg cells can block DC maturation and activation and proinflammatory cytokine production [68]. For instance, Treg cells can create IDO+ tolerogenic DCs by the CTLA-4/B7 interaction or by producing TGF-β and IL-10 [69–71]. Recent studies demonstrated that activated T cells can promote the immunosuppressive function of Fasexpressing regulatory DCs to secrete more IL-10 and IP-10, partially through FasL [72]. Using two-photon intravital imaging in vivo, a direct interaction between DC and B cells was clearly demonstrated, which can modulate each other’s function through antigen presentation and cytokine production [73]. Antigen bearing DCs can activate antigenspecific B cells, although several studies found that B cells can also transfer antigens to DCs [74]. Recently, human B cells were shown to be capable of transferring the BCR-targeted antigen to human DCs by scavenger receptor to induce a specific immunologic response [75]. In 3

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Fig. 2. Applying various regulators to fine tune DC function. DCs are a plastic lineage that can integrate signals to initiate immune responses and maintain self tolerance. The DC immune regulatory network include (1) multiple cross-talks between DCs and other cells from local microenvironment, such as interaction with other immune cells (T cell, B cells, NKT cells and granulocyte subtypes) and recognition of apoptotic and necrotic cell components and signals from stromal cells of spleen, liver, lung, intestine and tumor; (2) exposure of DCs to soluble regulators, such as anti-inflammatory factors and pro-inflammatory factors; and (3) cell-intrinsic regulators that control DC functions, such as membrane-associated receptors and intracellular molecules (ubiquitin related proteins, protein kinases, proteases and epigenetic factors).

autoantigens to autoreactive T cells, but production of anti-inflammatory cytokines like TGF-β and IL-10 can induce tolerance by various mechanisms, such as anergy, deletion of harmful T cells or activation of Treg cells [85,86]. However, if apoptotic cells can not be rapidly cleared by phagocytes in stressed or damaged tissues, they undergo secondary necrosis, and their plasma membrane becomes permeable, which causes the release of intracellular contents, including cytosolic DAMPs, to stimulate DC maturation [87,88]. For example, apoptotic and ER stress inducing agents can induce apoptosis of malignant cells accompanied with calreticulin (CRT) exposure which can function as an eat-me signal to stimulate the engulfment of DCs [89]. In addition to CRT, DAMPs release can promote DC maturation to initiate an antitumor immune response. So, exposure to apoptotic or necrotic cells is critical to modulate DC function between effective immunity and the induction of tolerance or immune inhibition [90]. Finally, various proteins and cytokines expressed by stromal cells in the microenvironment, soluble factors and cell-to-cell contact in the stromal microenvironment may perform key roles to regulate immune cells [91]. We found that stromal microenvironment in the spleen [92], liver [93], lung [94] and tumor microenvironment [95] can program DCs to differentiate into CD11bhighIalow regulatory DCs, which act as immunosuppressors via IL-10 [64], IP-10 [96] or arginase I. In the intestine, DCs constantly survey the luminal microenvironment, where the immune system lies in close proximity to the high local concentration of microbes and dietary antigens [97]. The dynamic

the presence of pathogens, invariant natural killer T (iNKT) cells can boost Th1 immunity by enhancing the maturation of pro-inflammatory DCs; however, in the absence of pathogens activated iNKT cells promote immune tolerance through the maturation of tolerogenic DCs [76]. A recent, accepted view is that different granulocyte populations, such as neutrophils, mast cells, eosinophils and basophils, are accessory cells that can significantly modulate DC function [77]. Depending on the mode of activation, neutrophils and mast cells have multiple immunomodulatory effects on DC-driven development of Th1, Th2 or Th17, which may be influenced via cell–cell contact or release of soluble mediators and granule contents [78]. Although our current knowledge on the crosstalk between DCs and eosinophils/basophils is still limited, eosinophils- and basophils-derived mediators can perform a regulatory role on DC function and promote Th2 cell polarization. In addition, the immune system is constantly exposed to apoptotic cells, generated in various tissues during normal development, homeostasis and pathogenic processes. Continued clearance of dying cells by either tissue-resident professional phagocytes, such as macrophages and immatureDCs, or neighbouring non-professional phagocytes is necessary to preserve whole-body homeostasis [79]. Although apoptotic cells maintain membrane integrity, membrane changes can be detected through various molecular features like MFG-E8 members [80], GAS6 [81], TIM4 [82], CD14 [83] and MerTK [84]. Under healthy conditions, immature DCs patrol the blood and recognize and engulf apoptotic cells that die during physiological turnover to continuously present 4

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Various intracellular signaling molecules contribute to the tight regulation of DC function, including ubiquitin-related proteins (A20 [124,125], FBXW7 [126] and CHIP [127]), protein kinases (CaMKII [128], SHP-1 [129]), rhomboid proteases Rhbdd3 and epigenetic factors (long noncoding RNA lnc-DC, miR-30b [130], methylcytosine dioxygenase Tet2, H3K27 methyltransferase Ezh2 [131], transcriptional factors STAT3 [132] and BLIMP1 [133]). For example, Rhbdd3 is critical to regulate DC activation and IL-6 production triggered by TLRs via K27-linked ubiquitination of the regulator NEMO. This process can control systemic inflammatory responses [134]. A long noncoding RNA (lncRNA) has been reported to be robustly induced in the process of human DC differentiation from monocytes (referred to as lnc-DC here after). lnc-DC is also highly expressed in human cDC subsets and functionally responsible for optimal human DC differentiation from monocytes and DC function. Cytoplasmic lnc-DC can promote STAT3 signaling, antigen uptake by Mo-DC and induce allogeneic CD4+ T cell proliferation and IL-12 production [135]. Recent, new insights into the functions of the epigenetic modifier Tet2 shows it recruits Hdac2 to specifically repress Il6 transcription via histone deacetylation, which provides a mechanism to resolve inflammation by preventing constant transcriptional activation at the chromatin level [136].

crosstalk between intestinal epithelial cells and DCs performs a key role in immune regulation to prevent inappropriate inflammatory responses to these mostly innocuous antigens. For example, both the tissue microenvironment and cell lineage drive the generation of regulatory αvβ8-expressing DCs specialized for TGF-β activation to facilitate Treg cell generation [98]. Thus, DCs can integrate signals from their microenvironment to induce regulatory rather than immunostimulatory activity in the host. 3.2. Soluble regulators Various soluble factors can regulate DC function and play an indispensable role to limit excessive immune responses via distinct mechanisms. Several observations demonstrated DCregs induction using well-known cytokines, such as IL-10 [99], TGF-β [63], VEGF [100], HGF [101] and VIP [102], as well as anti-inflammatory factors, such as complement components, Vitamin D3 [103] and retinoic acid [104]. IL10-modulated DCregs downregulate costimulatory molecules and MHC II, have a low capacity to secrete IL-6, IL-1β, TNF and IL-12 and upregulate the expression of inhibitory molecules like HLA-G [105]. Those IL-10-modulated DCs can induce anergic Treg cells to inhibit CD4+ or CD8+ T cell activation and function. Complement is a major arm of the host innate immune system against pathogen infections [106]. Evidence indicates that soluble C1q inhibits the expression of IL-12 and costimulatory molecules in DCs. These data suggest a tolerogenic property of C1q for T cell proliferation and IFN-γ production via DCs. However, immobilized C1q deposited in extracellular matrix around DCs can activate DCs [107]. Interestingly, DAMPs released by dying cells orchestrate antigenspecific immune responses. Most DAMPs, such as ATP, HMGB1 [108], heat shock proteins [109], uric acid [110] and genomic doublestranded DNA [111] have potential adjuvant properties through a DCdependent process. For example, ATP released from dying cancer cells during chemotherapy recruits myeloid cells into tumors and stimulates local differentiation of CD11c+CD11b+Ly6Chi inflammatory DCs [112]. Importantly, immunomodulatory DAMPs like adenosine [113] and PGE2 [114] can regulate the maintenance of immune tolerance. Recent studies demonstrate that released adenosine has a strong effect on DC differentiation and triggers DC generation that favors Th17 responses rather than those that promote Th1 responses [115].

4. DCs in infection and autoimmune diseases As the primary orchestrators in mammalian immunity, DCs control immune responses by initiating powerful inflammatory actions against external and internal threats, while simultaneously generating tolerance to self and harmless components [137]. Microbial pathogens represent an external threat and comprise invariant and specific microbial components normally absent in the healthy host. Once invading pathogens overcome the host’s physical and chemical barriers, DCs will immediately survey extracellular, vacuolar and cytosolic spaces to detect danger signals using specialized sensor proteins, such as TLRs, RIG I-like receptors, NOD-like receptors and cytosolic DNA sensors, that trigger distinct but shared signaling pathways [138]. After PRR recognizes a bacterial, viral, or fungal infection, DCs can evoke a strong, acute inflammatory response to infections, efficiently prime naïve T cells, activate memory T cells, and promote B cell activation to eradicate pathogens in a short term [139]. During the progression of early phase of sepsis, DCs can participate in the aberrant immune response by releasing various proinflammatory cytokines, including TNF-α and IFNγ [140]. During sepsis, DCs from lymphoid and nonlymphoid tissues are lost through apoptosis, but accelerate differentiation from monocytes [141]. Moreover, surface molecules (HLA-DR, CD83, CD86 and CXCR4) associated with DC function change. Concurrently, released inhibitory cytokines (IL-10 and IL-4) limit the strength of immune cell activation and expansion and negatively modulate inflammation to induce an immune tolerance status [142]. Numerous studies demonstrated that apoptosis, epigenetic regulation, Wnt and PPAR mediated mechanisms mediate the effect of sepsis on DC function [143]. As chronic inflammatory disorders, autoimmune diseases occur when the immune system recognizes self-antigens as foreign and immune homeostasis is severely disrupted, resulting in hyperactivity of both cellular and humoral immunity against these antigens [144]. Initially recognized for its function to initiate adaptive self-reactive responses, DCs in autoimmunity negatively regulate auto-reactive responses [145]. Altered DC distribution and/or disturbed key functions are a common feature of both systemic and tissue-specific autoimmune diseases, such as lupus erythematous (SLE), rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) [146]. To date, the main DC alterations that contribute to reduced tolerance in autoimmune diseases have been identified [144]. First, several quantitative analyses of DC subsets reveal that the distribution of DC populations changes in autoimmune diseases. In RA the number of circulating cDCs and pDCs decrease with a concomitant increased in DC number recruited by CCL20 in the synovial fluid [147,148]. CD14+CD1a+CD1c+

3.3. DC-intrinsic regulators Although numerous extrinsic factors have been identified that fine tune DC function, cell-intrinsic regulators, which translate or integrate these external cues into regulatory programs, are critical for DCs [116]. Intrinsic signal dysregulation is emerging as a fundamental feature in the pathogenesis of human diseases [117]. So, the diversity of roles these molecules perform reveals several possible mechanisms to control DC function throughout the signal network to evoke complex signaling platforms. Recent identification of membrane-associated receptors, such as integrin αvβ8 [118], Fas [119], CD11b, FcγRIIb [120] and Siglec-G, which induce DC regulatory functions, suggests an emerging model that functionally links external ligands with intracelluar DC signaling. Accumulating evidence demonstrates that signaling via inhibitory FcγRIIb on DCs is essential to maintain peripheral tolerance. Immune complexes can enhance tolerogenecity of immature DCs via FcγRIIb [121]. More recently, expression of Siglec-G, a member of the Siglec family, was significantly lower in CD8α+ DCs than CD8α− DCs and the molecule exhibited potent, negative regulation to inhibit DC cross-presentation by impairing MHC class I-peptide complex formation, which further indicates a functional link between Siglec-G and SHP-1 in DC phagosomes [122]. In addition, integrin CD11b negatively regulates TLR9triggered DC cross-priming by suppressing Notch1 expression and IL12p70 production [123]. 5

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inflammatory DCs, associated with RA pathogenesis because they induce TH17 cells, are also present in the synovial fluid of patients with RA [149]. Emerging evidence recently suggests that a rare subpopulation of DCs rich in perforin-containing granules (perf-DCs) could represent a regulatory cell subpopulation critical to protect against metabolic syndrome and autoimmunity [150,151]. Second, a lack of bridging molecules or functional scavenger receptor impairs phagocytosis of DCs in SLE to clear apoptotic cells [152]. Third, altered cytokine secretion by DCs, pDCs and inflammatory DCs can underlie the deleterious imbalance between TH1, TH2 and TH17 cells, as well as the generation of pathogenic autoantibodies [153,154]. Finally, defective DC migration from inflamed sites comprises a crucial mechanism in the development of specific autoimmune diseases, such as lupus nephritis and RA [155,156].

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