Myeloid dendritic cells: Development, functions, and role in atherosclerotic inflammation.

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Contents lists available at ScienceDirect

Immunobiology journal homepage: www.elsevier.com/locate/imbio

Review

Myeloid dendritic cells: Development, functions, and role in atherosclerotic inflammation Dimitry A. Chistiakov a,b,c , Igor A. Sobenin d,e,f , Alexander N. Orekhov d,e , Yuri V. Bobryshev d,g,h,∗ a

Department of Medical Nanobiotechnology, Pirogov Russian State Medical University, Moscow, Russia The Mount Sinai Community Clinical Oncology Program, Mount Sinai Comprehensive Cancer Center, Mount Sinai Medical Center, Miami Beach, FL, USA c Research Center for Children’s Health, Moscow, Russia d Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Moscow, Russia e Institute for Atherosclerosis Research, Skolkovo Innovative Center, Moscow, Russia f Laboratory of Medical Genetics, Russian Cardiology Research and Production Complex, Moscow, Russia g Faculty of Medicine, University of New South Wales, NSW, Sydney, Australia h School of Medicine, University of Western Sydney, Campbelltown, NSW, Australia b

a r t i c l e

i n f o

Article history: Received 27 October 2014 Received in revised form 7 December 2014 Accepted 22 December 2014 Available online xxx Keywords: Dendritic cells Myeloid dendritic cells Atherosclerosis Inflammation Immune reactions Arteries

a b s t r a c t Myeloid dendritic cells (mDCs) comprise a heterogeneous population of professional antigen-presenting cells, which are responsible for capture, processing, and presentation of antigens on their surface to T cells. mDCs serve as a bridge linking adaptive and innate immune responses. To date, the development of DC lineage in bone marrow is better characterized in mice than in humans. DCs and macrophages share the common myeloid progenitor called macrophage–dendritic cell progenitor (MDP) that gives rise to monocytoid lineage and common DC progenitors (CDPs). CDP in turn gives rise to plasmacytoid DCs and predendritic cells (pre-mDCs) that are common precursor of myeloid CD11b+ and CD8␣+ DCs. The development and commitment of mDCs is regulated by several transcription and hematopoietic growth factors of which CCr7, Zbtb46, and Flt3 represent ‘core’ genes responsible for development and functional and phenotypic maintenance of mDCs. mDCs were shown to be involved in the pathogenesis of many autoimmune and inflammatory diseases including atherosclerosis. In atherogenesis, different subsets of mDCs could possess both proatherogenic (e.g. proinflammatory) and atheroprotective (e.g. anti-inflammatory and tolerogenic) activities. The proinflammatory role of mDCs is consisted in production of inflammatory molecules and priming proinflammatory subsets of effector T cells. In contrast, tolerogenic mDCs fight against inflammation through arrest of activity of proinflammatory T cells and macrophages and induction of immunosuppressive regulatory T cells. Microenvironmental conditions trigger differentiation of mDCs to acquire proinflammatory or regulatory properties. © 2015 Elsevier GmbH. All rights reserved.

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Comparative analysis of two main subsets of human and mouse mDCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Development of mDCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Transcription factors that drive mDC-specific commitment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Transcription factors that drive commitment of mDC subsets. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Functions of mDCs in steady state conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of DCs in inflammation: phenotypic plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Regulatory DCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Myeloid DCs in atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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∗ Corresponding author at: Faculty of Medicine, University of New South Wales Sydney, NSW 2052, Australia. Tel.: +61 2 93851217; fax: +61 2 93851217. E-mail address: [email protected] (Y.V. Bobryshev). http://dx.doi.org/10.1016/j.imbio.2014.12.010 0171-2985/© 2015 Elsevier GmbH. All rights reserved.

Please cite this article in press as: Chistiakov, D.A., et al., Myeloid dendritic cells: Development, functions, and role in atherosclerotic inflammation. Immunobiology (2015), http://dx.doi.org/10.1016/j.imbio.2014.12.010


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Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Introduction Dendritic cells (DCs) comprise a heterogeneous population of blood-borne professional antigen-presenting cells characterized by ability to catch, process, and present antigens to T cells, which in turn recognize the antigen and induce the antigen-specific immune response (Banchereau and Steinman 1998). Therefore, DCs are key players in induction of immune response and link together innate and humoral immunity. Depending on the origin, location, and function, DCs could be divided to several subpopulations. After leaving the bone marrow and entering the bloodstream, DC progenitors give rise to resident and migratory DCs that complete their differentiation. DCs could reside in lymphoid and non-lymphoid tissues where they engulf antigens and present them to local T cells. In peripheral tissues, migratory non-lymphoid tissue DCs patrol the circulatory system where they uptake antigens and migrate to lymph nodes to present antigens to T lymphocytes (Broggi et al. 2013). In the periphery, migratory DCs are presented as three main subpopulations. Plasmacytoid DCs (pDCs) are characterized with a relatively low expression of human leukocyte antigen (HLA) class I and class II molecules, high surface expression of Toll-like receptor (TLR)-7 and -9, and production of high amounts of Type I interferons (IFNs) (Haniffa et al. 2013). pDCs play a pivotal role in induction of antiviral and antibacterial responses (Chistiakov et al. 2014a). Human pDCs express the surface markers CD123, blood dendritic cell antigen (BDCA)-2 (CD303), and BDCA-4 (CD304), but do not express high levels of CD11c or CD141 that separates them from conventional DCs (cDCs) (Dzionek et al. 2000). In humans, myeloid (or conventional) DCs (mDCs) are presented by two main subpopulations including CD1c/BDCA-1+ cells and CD141/BDCA-3+ cells that account for ∼50% and 5–10% of a total peripheral DC population respectively (MacDonald et al. 2002). Murine counterparts of human DCs are shown in Table 1 (Robbins et al. 2008). Mouse and human DCs (and pDCs especially) were shown to share many evolutionarily conserved molecular pathways (Robbins et al. 2008) suggesting for significant functional preservation of DCs among mammals. DCs were shown to play a crucial role in various pathologic conditions involving inflammatory and autoimmune background such as atherosclerotic disease (Chistiakov et al. 2014b). In atherosclerosis, human DCs could present self-antigens to CD4+ , CD8+ , and natural killer (NK) T cells in HLA class II-, HLA class I-, and CD1d-dependent manner respectively. This indeed leads to the activation of naïve T cells, mainly toward the proinflammatory phenotype (Koltsova et al. 2012). However, the anti-inflammatory and immunosuppressive response also occurs in atherosclerosis.

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Regulatory DC subsets contribute to the anti-inflammation, which is atheroprotective (Schmidt et al. 2012). Previously, we considered developmental and functional aspects of pDCs, with emphasis on their contribution in atherosclerosis (Chistiakov et al. 2014a). In this review, we characterize development and function of mDCs and consider their role in atherogenesis. Comparative analysis of two main subsets of human and mouse mDCs For human and murine DCs, a list of surface markers and receptors essential to distinguish mDCs from pDCs is presented in Table 2. Both human and mouse mDCs express myeloid markers CD13 and CD33 and CD32, an immune inhibitory Fc receptor (Guilliams et al. 2014). Human migratory CD141+ mDCs express TLR3 and release large amounts of interleukin (IL)-12 and IFN-␤ in response to activation with poly(I:C), a mimic of double stranded RNA and ligand for TLR3 (Kaisho 2012). CD141+ mDCs express C-type lectin domain 9A (CLEC9A), a receptor sensing necrotic cell antigens (Sancho et al. 2009) and hence are capable to engulf dead cells and cross-present cell-associated and soluble antigens upon activation of TLR3 ligands (Iborra et al. 2012; Zelenay et al. 2012). Both human CD141+ mDCs and mouse CD8␣+ mDCs coexpress TLR3, CLEC9A, and chemokine (C motif) ligand receptor 1 (XCR1) (Poulin et al. 2010). Compared to other DC subpopulations, XCR1 was shown to represent the most selective marker for both CD141+ and CD8␣+ mDCs (Crozat et al. 2010). In addition, both mDC subsets were found to share expression of transcription factors (interferon regulatory factor (IRF) 8 and basic leucine zipper transcription factor, ATF-like 3 (BATF3)) and surface markers such as nectin-like molecule 2 (Necl2) and langerin (CD207). Like mouse CD8␣+ mDCs, human CD141+ DCs lack expression of IRF4, CD11b, and TLR7 (Iborra et al. 2012). Human hematopoietic progenitors differentiate to CD141+ DCs in the presence of FMS-like tyrosine kinase 3 ligand (Flt3L), a key master regulator of DC development. Down-regulation of BATF3 in hematopoietic progenitors was observed to prevent differentiation of CD141+ DCs but not CD1c+ DCs (Poulin et al. 2012) thereby indicating the relationship in the ontogeny of human CD141+ DCs and mouse CD8␣+ mDCs. Furthermore, both DC subpopulations are functionally related due to superior capacity to antigen crosspresentation, e.g. ability to present an extracellular antigen not in a classical major compatibility complex (MHC) class II-dependent manner, but through a MHC-I-mediated presentation mechanism (Bachem et al. 2010). However, despite many phenotypical and functional similarities between these mDC subsets, there are some differences. For

Table 1 Major subsets of circulating human and mouse DCs. Dendritic cell subset

Plasmacytoid Myeloid (subset 1) Myeloid (subset 2)

Surface markers Human

Mouse

CD11c+ CD123+ BDCA-2+++ BDCA-4+++ TLR7+++ TLR9+++ CD1clow CD141clow CD1c/BDCA-1+++ CD11c++ TLR2+++ TLR4+++ CD141/BDCA-3+++ CD11b− CD11c++ CLEC9A+ XCR1+ TLR3+++ TLR10+++

CD11c+ B220+ mPDCA-1+++ CD11b− Clec12a+++ SiglecH+++ Tlr7+++ Tlr9+++ CD11b+++ CD209a+ Tlr7+ Tlr9+ Tlr12+++ Tlr13+++ CD8␣+++ Clec9a+++ Xcr1+ Ly75+++ Tlr3++ Tlr11+++

BDCA, blood dendritic cell antigen; CLEC9A, C-type lectin domain 9A; Ly75, Lymphocyte antigen 75; mPDCA-1, mouse plasmacytoid dendritic cell antigen-1; TLR, Toll-like receptor; XCR1, chemokine (C motif) ligand receptor 1; SiglecH, sialic acid-binding immunoglobulin H-type lectin.


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Table 2 Surface markers and receptors that distinguish human and mouse mDCs from pDCs. Marker/receptor

Expression in mDCs Human

Mouse

CD1c/BDCA-1 CD11b/Mac-1/ITGAM/CR3

+ −

− +

CD141/BDCA-3

+

−

CD8␣ CD14

− +

+ +

CD13/LAP1 CD33/Siglec-3 CD32 CD45RO CD209/DC-SIGN

+ + + + +

+ + + + +

CD205/Ly75 CLEC9A

− +

+ +

XCR1/CCXCR1 TLR2/CD282

+ +

+ +

TLR3/CD283 TLR4/CD284

+ +

+ +

TLR11 TLR12 TLR13

− − −

+ + +

Function

Mediates presentation of non-peptide antigens to T cells Regulates leukocyte adhesion and migration, contributes to phagocytosis, cytotoxicity, chemotaxis, binds inactivated complement component C3b Thrombomodulin that binds thrombin and participates in inhibition of fibrinolysis; regulates C3b inactivation by factor 1 Serves as co-receptor for T-cell receptor and is involved to antigen recognition Pattern recognition receptor that acts along with TLR4 and Ly96 to sense bacterial LPS and lipoteichoic acid Alanine aminopeptidase N, which is involved in the metabolism of regulatory peptides Lectin receptor that contributes to conducting negative immune signaling Fc receptor that down-regulates antibody production in the presence of IgG Protein tyrosine receptor phosphatase C isoform that controls immune activation C-type lectin receptor involved in DC rolling on the epithelial surface and recognition of pathogen mannose type carbohydrates by CD4+ T cells Antigen delivery for presentation to MHC class II and cross-presentation to MHC class I C-type lectin involved in recognition of ubiquitous preformed acid-labile protein associated ligand(s) that are exposed on necrotic cells Chemokine receptor that binds XCL1 and XCL2 and attracts T cells Pattern recognition receptor that cooperates with LY96 to mediate the innate immune response to bacterial lipoproteins and other microbial cell wall components from Gram-positive bacteria. Cooperates with TLR1 or TLR6 to mediate the innate immune response to bacterial lipoproteins or lipopeptides Pattern recognition receptor that senses double stranded viral RNA Pattern recognition receptor that cooperates with LY96 and CD14 to recognize LPS from Gram-negative bacteria Pattern recognition receptor that recognizes bacterial flagelin and protozoan profillin Pattern recognition receptor that recognizes protozoan profilin Pattern recognition receptor that recognizes protozoan profilin

BDCA, blood dendritic cell antigen; CD, cluster of differentiation; CLEC9A, C-type lectin domain 9A; CR3, complement receptor 3; DC-SIGN, dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin; Ig, immunoglobulin; ITGAM, integrin ␣M ; LAP1, l-alanine aminopeptidase 1; LPS, lipopolysaccharide; Ly, lymphocyte antigen; Mac-1, macrophage-1 antigen; MHC, major histocompatibility cluster; TLR, Toll-like receptor; Siglec-3, sialic acid-binding immunoglobulin-type lectin-3; XCL, chemokine (C motif) ligand.

example, mouse CD8␣+ DCs express TLR9 while human CD141+ DCs do not (Iborra et al. 2012). In addition, CD8␣+ DCs produce TLR11, e.g. a pattern recognition receptor (PRR) that is able to sense microbial filamentous proteins such as bacterial flagellin and profilin of Toxoplasma gondii, an intracellular protozoan parasite (Yarovinsky and Sher 2006). TLR11-mediated pathway is dysfunctional in human innate immunity due to the lack of the functional product transcribed from the human TLR11 gene (Lauw et al., 2005). It was suggested that human TLR11 gene could be repressed thanks to its putative interaction with profilin expressed in humans (Balenga and Balenga 2007), Indeed, this could explain high prevalence of toxoplasmosis in humans infecting up to a third of the world’s population (Salazar Gonzalez et al. 2014). Compared to CD141+ mDCs, CD1c+ mDCs also cross-react with CD8+ T cells upon TLR3 stimulation but with less efficiency (Mittag et al. 2011). Human CD1c+ mDCs produce all range of TLRs (TLR110) except for TLR9 whereas CD141+ mDCs highly express only two TLRs (TLR3 and -10) and do not express TLR4-7 and TLR9 (Hémont et al. 2013). Compared to CD141+ DCs, CD1c+ mDCs produce a variety of cytokines (tumor necrosis factor (TNF)-␣, IL-1␤, IL-6, IL-8, and IL-12) and chemokines (C-C motif chemokine (CCL)-3, -4, -5, and (C-X-C-motif chemokine (CXCL-10)) in response to stimulation of TLR3 (Jongbloed et al. 2010; Hémont et al. 2013). Upon TLR3 stimulation, blood CD141+ DCs secrete IL-12, IFN-␤, IFN-␭, CCL-5, and CXCL-10 (Lauterbach et al. 2010; Hémont et al. 2013) while skin CD141+ DCs release TNF-␣ and CXCL-10 (Nizzoli et al. 2013). Genome-wide transcriptome analysis showed that human CD1c+ mDCs are developmentally related to mouse CD11b+ mDCs (Robbins et al. 2008). However, compared to human counterparts, murine CD11b+ mDCs produce a broader repertoire of TLRs including TLR7 (Doxsee et al. 2003), TLR12, and TLR13 (Mishra et al. 2008).

Development of mDCs DC development was considered in details in two recent reviews (Merad et al. 2013; Chistiakov et al. 2014a). Briefly, the current paradigm suggests that pDCs and mDCs in humans and mice have a common myeloid progenitor that gives rise to monocytoid lineage and committed DC progenitors (CDPs) in the bone marrow (Liu and Nussenzweig 2010). In mice, Naik et al. (2007) reported finding of CD11c− MHCII− DC progenitor that expresses on its surface protein kinase Flt3, a receptor for Flt3L (D’Amico and Wu 2003; Naik et al. 2010). This progenitor further differentiates to CDP (CD11c+ MHCII− Flt3+ ), a common DC precursor that gives rice to pDCs and pre-mDCs (Onai et al. 2007). CDP was shown to express CSF1R, a receptor for macrophage colony-stimulating factor (MCSF), a hematopoietic growth factor that drives differentiation of CDP to pDCs and pre-mDC, a common precursor of myeloid CD11b+ and CD8␣+ DCs (Diao et al. 2006; Fancke et al. 2008; O’Keeffe et al. 2010). Developmental mechanisms of human DCs are less clear compared to those in mice. It was shown that human pDCs and mDCs have a common progenitor that gives rise to both DC subsets after separation to the lymphoid or the myeloid lineage in hematopoiesis (Ishikawa et al. 2007). However, there are many gaps in our understanding of human DC developmental stages because human hematopoietic DC progenitors analogous to mouse common macrophage–dendritic cell progenitors (MDPs) and premDCs were not isolated yet from the bone marrow. Unlike mouse hematopoietic stem cells (HSCs), CD34+ human HSCs produce MHC class II molecules on their surface and this complicates finding early human DC precursors (Majumdar et al. 2003). A coordinated work of multiple transcription factors plays a critical role in supporting normal release of DC developmental


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and differentiation program. A transcription factor network essential for commitment of DC-specific lineage at early hematopoietic developmental stages was extensively reviewed (Satpathy et al. 2011; Belz and Nutt 2012; Merad et al. 2013; Chistiakov et al. 2014a). Here, we will focus on the characterization of transcription factors that drive mouse DC differentiation at late developmental stages including commitment of pre-mDCs from pDCs and further distinguishing between CD8␣+ and CD8− mDC subsets. Transcription factors that drive mDC-specific commitment Interestingly, a transcriptome analysis showed that mouse CDP is already primed for preferential differentiation toward pDCs due to the moderate expression of pDC transcription factors such as E2-2 (or transcription factor TCF4), B-cell lymphoma/leukemia 11A (Bcl11a), and Runt-related transcription factor 2 (Runx2). In contrast, CDPs had very low levels or no expression of mDC-specific factors such as Batf3, B-cell lymphoma 6 protein (Bcl6), and DNAbinding protein inhibitor Id2 (Felker et al. 2010). These data suggest that CDP is set to “default” into the pDC lineage unless a stimulus is received to induce Id2 whose activation appears to play a key role in transition from CDP to pre-mDC associated with down-regulation of pDC-specific transcriptional program. The NH2-terminal region Bcl6 is capable to bind to the silencing mediator of retinoid and thyroid receptor protein (NCOR1) and recruit the histone deacetylase complex to silencer regions of target genes to repress expression of these genes (Wong and Privalsky 1998). Therefore, Bcl6 acts as a sequence-specific transcriptional repressor (Seyfert et al. 1996). No expression of this transcriptional regulator was found in mouse CDPs and early hematopoietic progenitors. However, Bcl6 expression was detected in pre-mDCs and all myeloid DC subsets, with greatest levels in CD8␣+ cDCs (Zhang et al. 2014). Bcl6 was shown to support differentiation of CDPs toward myeloid DCs (Ohtsuka et al. 2011). In Bcl6-deficient mice, the numbers of spleen CD4+ mDCs and CD8␣+ cDCs, but not of pDCs, were significantly decreased. DC progenitors derived from Bcl6-deficient mice could differentiate to pre-mDCs in the presence of Flt3L but were more apoptotic compared to pre-mDCs from normal mice due to increased expression of p53, a target for Bcl-6 (Ohtsuka et al. 2011). These data again suggest for essential role of Bcl6 in development of mDCs through increasing mDC survival by repression of apoptotic genes such asp53, ataxia telangiectasia and Rad3-related protein (ATR), p21/Cip1, and E1A binding protein p300 (EP300) and inhibition of terminal differentiation factors including Irf4 and PR domain zinc finger protein 1 (PRDM1) (Basso and Dalla-Favera 2012). Interestingly, transcription regulators Irf4 and Irf8 possess different effects on Bcl6 induction: while Irf8 stimulates its expression (Lee et al. 2006), Irf4 supporting pDC-specific commitment, in contrast, inhibits expression of Bcl6 (Lossos 2007). IFN-␣ that promotes Flt3L-mediated pDC development also suppresses Bcl6 (Salamon et al. 2012). In fully matured and activated mDCs, expression of Bcl6 is down-regulated (Pantano et al. 2006) indicating this factor is responsible for the myeloid-specific commitment in DC development but not involved in the final maturation of mDCs. E2-2 is a member of a family of transcription factors (called E proteins) that share a conserved basic helix-loop-helix (HLH) motif and bind to a consensus DNA sequence CANNTG called E-box (Chaudhary and Skinner 1999). Overexpression of E2-2 in progenitor cells was found to support predominant generation of pDCs, with a costimulating effect of an Ets subfamily transcription factor Spi-B (Nagasawa et al. 2008). Further studies confirmed a key role of E2-2 in commitment of pDCs because this factor is involved in direct stimulation of expression of a pDC-specific gene set including transcription factors involved in pDC development (Spi-B, Bcl11a, Irf8) and function (Irf7) (Cisse et al. 2008) and maintenance of core

phenotypic and functional properties of pDCs (Ghosh et al. 2010). E2-2 also appears to down-regulate mDC-specific developmental program (Ghosh et al. 2010). Id2 belongs to the inhibitor of DNA binding (ID) family whose members contain a HLH domain but not a basic HLH domain (Hara et al. 1994). ID inhibitors specifically block transcriptional activity of factors that have basic HLH motif (Sun et al. 1991). Id2 overexpression was found to lead to the suppression of pDC development (Spits et al. 2000). Granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced expression of Id2 resulted in enhanced development of CD8␣+ mDCs but not other subsets suggesting that Id2 may be responsible for commitment of this mDC subset (Hacker et al. 2003). In Id2-deficient mice, derepression of many genes associated with the pDC-specific developmental program was observed in developing DCs (Robbins et al. 2008). Depletion of E2-2 in mature pDCs led to the arrest of pDC-specific transcriptome and induction of expression of mDC-specific genes including Id2 (Ghosh et al. 2010). These findings suggest that Id2 inhibits activity of E2-2 and switches CDP differentiation toward mDCs. It should be noted that Id2 function could be compromised by myeloid translocation gene 16 (Mtg16)/Eto2, a transcriptional corepressor of the ETO protein family, which suppresses expression of Id2. Mouse pDCs lacking Mtg16 were found to have aberrant phenotype associated with the induction of expression of myeloid marker Cd1b and enhanced differentiation of pre-mDCs to CD8␣+ mDCs (Ghosh et al. 2014). In humans, GM-CSF and Flt3L were shown to induce the transcriptional mediators Id2 and E2-2 and control DC lineage diversification in a signal transducer and activator of transcription (STAT)-dependent manner. STAT5 mediates GMCSF-dependent expression of Id2 and developmental switch to the generation of CD103+ mDCs while STAT3 directs Flt3L-dependent expression of E2-2 and triggers formation of pDCs (Li et al. 2012). Transforming growth factor (TGF)-␤1 was reported to influence the pathway of CDP differentiation by induction of predominant generation of mDCs through activation of Id2 and cDC instructive factors such as Irf4 and v-rel avian reticuloendotheliosis viral oncogene homolog B (RelB), an activator of transcription nuclear factor (NF)␬B (Felker et al. 2010). Indeed, expression levels and activity Id2 and E2-2 trigger CPD developmental diversification and balance between these lineage-specific transcriptional regulators controls the fate of CDP differentiation toward either pDCs or mDCs. Transcription factors that drive commitment of mDC subsets The role of transcription factors involved in terminal differentiation of a common precursor of myelod DCs to different cell subsets was mainly investigated in mice. The in-depth analysis of the transcriptome of murine pre-mDC performed recently by Miller et al. (2012) revealed a group of transcripts (called a ‘core cDC signature’), which were markedly enriched in mDCs compared to other hematopoietic cell subsets. This group includes Ccr7 (a chemokine receptor that drives mDC migration to the draining lymph nodes) (Ohl et al. 2004), zinc finger and BTB domain containing 46 (Zbtb46; a transcription factor essential for mDCspecific commitment (Satpathy et al. 2012) and prevention of activation of mDCs in the steady state) (Meredith et al. 2012b), Flt3, and also alanine aminopeptidase (Anpep/Cd13; a myeloid marker) and nectin-1 (Pvrl1/Cd111, a hematopoietic progenitor marker). Indeed, CCr7, Zbtb46, and Flt3 represent ‘core’ genes responsible for development and functional and phenotypic maintenance of myeloid DCs. Irf4 and Irf8 appear to play a primary role in induction of different mDC subsets. IRF-4 was observed to be essential for formation of CD4+ mDCs while IRF-8 controls development of CD8␣+ mDCs (Fig. 1) (Tsujimura et al. 2003; Suzuki et al. 2004). Both IRFs supported development of CD4− CD8␣− DCs. Interestingly,


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E2-2, Bcl11A, Runx2 Irf4, Irf8 Mtg16, STAT3 M-CSF Flt3L IFN-I

Tolerogenic smuli (e.g.TGF-β,IL-10, PGE2)

pDC

5

Premature mDC

Proinflammatory smuli(e.g. PAMPs, DAMPs, inflammatory cytokines and chemokines)

CD8α+ mDCs

CDP Regulatory mDC M-CSF GM-CSF Id2, Ba3, Bcl6 Flt3L Zbtb46 TGF-β1 STAT5

Smulatory mDC

Flt3L Irf8 Id2, Ba3, Nfil3 Pre-mDC

CD4+ mDCs

IL-10, IL-27, TGF-β, IDO, PD-1

Irf4 RelB, Rbp-j TRAF6 GM-CSF Inducon of Tregs

IL-6,IL-12,IFN-γ,TNF-α, CCL2,CCL5

Differenaon and Arrest or impaired Arrest of proliferaon of proliferaon of Th1, funcon of Tregs CD4+ and CD8+Tcells Th2 and Th17cells

Fig. 1. Cytokines, hematopoietic growth factors, and transcription factors regulating late developmental stages of mouse DCs and commitment of pDCs, CD4+ mDCs, and CD8␣+ mDCs. Batf3, basic leucine zipper transcription factor, ATF-like 3; Bcl6, B-cell lymphoma 6 protein; CDP, committed dendritic cell progenitor; E2-2, E family transcription factor 2; Flt3L, FMS-like tyrosine kinase 3 ligand; GM-CSF, granulocyte-macrophage colony-stimulating factor; Id2, inhibitor of DNA binding 2; IFN-I, type I interferons; Irf4, interferon regulatory factor; M-CSF, macrophage colony-stimulating factor; mDC, myeloid dendritic cell; Mtg16, myeloid translocation gene 16, Nfil3, nuclear factor-IL-3 regulated; pDC, plasmacytoid dendritic cell; pre-mDC, common myeloid dendritic cell precursor; Rbp-j, recombining binding protein suppressor of hairless; RelB, v-rel avian reticuloendotheliosis viral oncogene homolog B; Runx2, Runt-related transcription factor 2; STAT3, signal transducer and activator of transcription; TGF-␤1, transforming growth factor-␤1; Zbtb46, zinc finger and BTB domain containing 46.

Fig. 2. Stimulatory and regulatory mDCs. Myeloid DCs are a plastic lineage capable to acquire regulatory or stimulatory properties depending on the stimuli coming from the local microenvironment. Proinlammatory signals such as inflammatory cytokines and chemokines and presence of pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) drive preferential differentiation of immature mDCs to stimulatory mDCs. Mature stimulatory DCs secrete a range of immunostimulatory cytokines and chemokines that prime differentiation of naïve T cells to effector T cells mostly presented by proinflammatory Th1 and Th17 cells. Stimulatory mDCs are also able to inhibit or impair immunosuppressive function of Tregs. In contrast, anti-inflammatory microenvironment such as transforming growth factor (TGF)-␤, interleukin-10 (IL-10), and prostaglandin E2 (PGE2 ) trigger induction of mDCs with regulatory properties. These tolerogenic mDCs possess immunoinhibitory properties and produce anti-inflammatory cytokines IL-10 and TGF-␤ and immunoregulatory molecules such as indoleamine 2,3-dioxygenase (IDO) and programmed cell death protein 1 (PD-1) ligand capable to suppress activation and proliferation of effector T cells and efficiently induce Tregs.

GM-CSF-mediated DC differentiation depends on IRF-4, whereas Flt3L-mediated differentiation depends mainly on IRF-8 (Tamura et al. 2005). Both IRFs were shown to have an overlapping activity and stimulate a common process of DC development. Nonetheless, each IRF also possesses a distinct activity to stimulate subsetspecific gene expression (Fig. 2). For CD8␣+ mDCs development, IRF-8 is a central player, which initiates the transcriptional program specific for this subset. Irf-8 alone was found to be essential for launching CD8␣+ DC commitment even in the absence of transcriptional regulators Id2, nuclear factor-IL-3 regulated (Nfil3), and Batf3. The Irf-8-induced DCs displayed several characteristics of CD8␣+ mDCs such as advanced antigen cross-presentation and expression of specific markers including CD24, Tlr3, Xcr1, and Clec9A (Seillet et al. 2013). Irf-8 stimulates expression of Id2 and Batf3 that then activate transcriptional networks leading to generation of CD8␣+ DCs. Moreover, Id2 and Batf3 can cooperate to each other in realization of the CD8␣+ DC-specific developmental program (Jaiswal et al. 2013). Transcription factor Nfil3 was shown be essential for development of CD8␣+ mDCs. In fact, this factor supports development of CD8-positive hematopoietic cell lineages including NK cells (Male et al. 2012). Nfil3-deficient mice showed marked depletion of NK cells and CD8␣+ mDCs not for CD8␣-mDCs and pDCs. Furthermore, in Nfil3-deficient mice, CD8␣+ DC development and function (e.g. cross-presentation) were impaired while CD8+ T lymphocytes were defective in response to a cell-mediated antigen (Kashiwada et al. 2011). These findings support a key role of Nfil3 in the development of CD8␣+ mDCs. This factor serves as a transcriptional regulator that binds as a homodimer to activating transcription factor (ATF) sites in multiple cellular promoters. In the CD8␣ gene, a promoter contains ATF-binding motifs and therefore could be regulated by members of the ATF family transcription factors (Gao and Kavathas 1993) including basic ATF-like factors such as Batf and

Batf3 (Kuroda et al. 2011). Indeed, Nfil3 could control CD8␣+ DC differentiation in part via Batf3 (Kashiwada et al. 2011). In contrast to Nfil3, RelB cooperates with Irf4 in priming development of CD4+ mDCs. The Irf4 gene is one of the targets of Nfil3 (Suzuki et al. 2004). RelB is induced in pre-mDCs and continue to be mainly expressed by CD4+ mDCs. RelB deletion in mice leads to significant depletion of CD4+ mDCs but does not affects CD8␣+ mDC and pDC populations (Burkly et al. 1995; Wu et al. 1998). TRAF6, a member of TNF receptor associated factor (TRAF) protein family, is involved in the regulation of CD4+ mDC development and maturation (Kobayashi et al. 2003). In TRAF-6-deficient mice, CD4+ CD8␣− DC subset is almost absent suggesting for the critical role of this transcription factor in their development (Chiffoleau et al. 2003). Recombining binding protein suppressor of hairless (Rbp-j), a transcription factor and homolog of Drosophila Suppressor of Hairless, is involved in mediating the canonical signaling from all Notch receptors (Hsieh et al. 1996). Rbp-j was found to regulate survival of CD4+ mDCs since Rbp-j-deficient mice lack over a half of a CD4+ mDC population due to enhanced apoptosis (Caton et al. 2007). Notch1 could suppress apoptosis via Rbp-j-mediated suppression of expression of SWI3-related gene 3 (SRG3), a senescence-related gene encoding a mouse homolog of yeast transcription factor SWI3 (Jang et al. 2006). DC-specific disruption of Rbp-j was shown to affect cytoskeleton organization that in turn reduces capacity of DCs to activate T cells (Chen et al. 2013). Rbp-j probably could contribute to the tissue-specific differentiation of DCs through binding to E2-2, a basic HLH transcription factor (Tanigaki and Honjo 2010). The current information about a role of transcription factors in terminal differentiation of human mDC subsets is scarce. BATF3 was shown to be highly expressed in CD141+ CLEC9A+ XCR1+ mDCs (Poulin et al. 2012) and be involved in their commitment. XCR1-positive human DCs that are responsive to TLR3-mediated stimulation with poly(I:C) acid and possess functional properties




of CD141+ mDCs (e.g. enhanced ability to cross-presentation) could be induced from circulating CD34+ hematopoietic progenitors (Silk et al. 2012; Balan et al. 2014). Like mouse CD8␣+ Xcr1+ DCs, the development of human XCR1+ DCs was dependent on transcription factor BATF3 (Bachem et al. 2012; Becker et al. 2014). Indeed, XCR1 could be considered as a specific cell marker of DC subsets capable to efficiently cross-present foreign antigens (Bachem et al. 2012). On the other hand, BATF3 is crucial for the commitment of mouse and human XCR1+ DCs whose properties largely overlap with those of human CD141+ mDCs and murine CD8␣+ mDCs. It is likely that humans and mice share many similarities between transcriptional mechanisms of terminal differentiation of specific mDC subsets. Indeed, the knowledge of molecular pathways that regulate developmental specification of mDC subsets in mice could be applicable for better understanding of mechanisms of terminal differentiation of human mDCs. No doubt, late developmental stages of human DCs should also have unique transcriptional signatures that are absent in murine hematopoiesis. However, extensive gaps existing in our knowledge of human DC developmental stages seriously hamper our modern understanding of the transcriptional control of commitment of distinct DC subsets and hence should be filled in the future.

Functions of mDCs in steady state conditions A classical DC function, a characteristic of mDCs, is consisted in catching, processing, and presenting of an antigen to a naïve CD4+ T cell that results in T-cell mediated antigen recognition and T cell activation. To stimulate CD8+ T cells, cooperation with activated CD4+ T helper (Th) cells or TLR activation is required (Hivroz et al. 2012). Activation of CD4+ T cells mediated by mDCs results in their polarization toward proinflammatory (Th1, Th17), anti-inflammatory (Th2) or immunoregulatory (regulatory T cells, Tregs) phenotype. MHC class I-dependent mechanism of crosspresentation of exogenous antigens is essential for stimulation of CD8+ T cells (Joffre et al. 2012). Human CD1c+ and CD141+ mDCs have an equal capacity to uptake antigens and are similarly efficient in their presentation to CD4+ and CD8+ T cells (Jongbloed et al. 2010). Compared to monocyte-derived DCs, both mDCs and pDCs have a superior ability to process antigen associated with preservation of T-cell epitopes and limited lysosomal degradation due the low proteolytic activity (McCurley and Mellman 2010). In contrast, monocyte-derived DCs like macrophages rapidly degrade internalized proteins due to the high levels of lysosomal proteases (Delamarre et al. 2005). In immature mDCs, lysosomal function is reduced. During maturation, mDCs acquire an advanced capacity to form and accumulate peptide-MHCII complexes and enhance lysosomal function through the activation of vacuolar proton pumps followed by lysosomal acidification, stimulation of proteolytic activity, and dramatic structural reorganization of lysosomes (Trombetta et al. 2003). Even in immature mDCs, CD1 molecules are able to efficiently transfer and present lipid and glycolipid antigens to T cells like mature DCs. This process is independent on MHC class II molecules, which present peptide antigens and whose surface expression is markedly increases along with maturation while CD1 surface expression is either slightly increased (for CD1b and CD1c) or decreased (for CD1a) (Cao et al. 2002). Immature DCs synthesize large amounts of MHC class II molecules that are targeted to late endosome and lysosomes (referred as lysosomal MHC class II compartments) where they unproductively reside with engulfed antigens (Chow et al. 2002). After stimulation with microbial products or inflammatory mediators, antigen endocytosis becomes suppressed followed with increase in expression of co-stimulatory molecules and trafficking

of newly formed immunogenic MHC II-peptide complexes toward the cell surface (van der Wel et al. 2003). Immature DCs circulate in blood and could migrate to peripheral tissues to uptake antigens from infected, apoptotic, and necrotic cells. mDCs have a broad repertoire of receptors capable to bind and recognize a variety of antigens. C-type lectin receptors such as CD206, DEC205 or CLEC4A directly take antigens and then provide them to the antigen-processing machinery located in cytoplasmic endosomes (Villadangos and Schnorrer 2007). Pathogen-associated molecular patterns (PAMPs) such as bacterial and viral products could be sensed by PRRs such as TLRs, retinoic acid-inducible gene (RIG)-like helicases, and nucleotide-binding oligomerization domain (NOD)-like receptors. Other PRRs including S100A/B proteins and high mobility group box 1 (HMGB1) are involved in the recognition of damage-associated molecular patterns (DAMPs) released by injured cells (Tang et al. 2012). Trafficking of MHC-antigen complexes to the DC surface is accompanied with rise in expression of co-stimulators such as CD80/B7-1 and CD86/B7-2. Human mature DCs express on their surface higher levels of CD40, CD54/intercellular adhesion molecule 1 (ICAM-1), CD80, and HLA-DR (Reis 2006). PRR-mediated catching of antigens stimulates mDC migration to lymph nodes to present antigens to T and B cells (Hemmi and Akira 2005). Migration is controlled by CCR7, a homing receptor that directs DC migration toward increase in concentration gradient of its ligands, chemokines CCL19 and CCL21 (Riol-Blanco et al. 2005). MHC-mediated presentation of processed antigens on the surface of mDCs in the presence of co-stimulating molecules to T cells and B cells is central in the induction of immune response. For T cell activation, at least 4 stimulatory signals should be performed during formation of the immune synapse. First signal represents an interaction between an antigen and T cell receptor mediated by MHC molecules. Binding of CD54 and lymphocyte function-associated antigen 1 (LFA-1) located on the DC and T cell surface respectively strengthens cell-cell contacts. Interaction between DC-associated CD80/CD86 and CD28 expressed on T-cell surface provides the so-called signal two. Binding of DC-associated CD40 to T-cell CD40L stimulates IL-12 production by mDCs and causes Th1 polarization of activated T cell. Increased release of IFN-␥ by mDCs is necessary for activation of cytotoxic T cells and macrophages (Fooksman 2014).mDCs are thought to play a central role in presenting antigens and releasing cytokines that can prime differentiation of naïve T cells and drive polarization of CD4+ Th cells. Non-stimulated human CD141+ mDCs were shown to have a preferential ability to push naïve CD4+ T cells toward the proinflammatory Th1 phenotype (Jongbloed et al. 2010). This may be explained by elevated surface levels of TLR3 and increased production of proinflammatory mediators such as IL-12, C-X-C motif chemokine 10 (CXCL-10), and IFN-␤ by mature CD141+ mDCs. In support of the proinflammatory nature of migratory CD141+ mDCs ‘by default’, stimulation of TLR3 caused enhanced generation of mCDs that secreted IFN-␥, a proinflammatory cytokine (Hémont et al. 2013). Meanwhile, cDCs resided in lymph nodes showed ability to prime naïve T cells to both Th1 and Th2 (e.g. anti-inflammatory) subsets (Klechevsky et al. 2008; Segura et al. 2012). Compared to CD141+ mDCs, non-stimulated human CD1c+ DCs from peripheral blood were found to display an advanced capacity to induce differentiation of Th17 cells due to increased production of IL-23, a cytokine that is critical for Th17 development and maintenance of Th17-specific cell phenotype (Schlitzer et al. 2013). As mentioned above, unstimulated human CD141+ mDCs like mouse CD8␣+ mDCs are the most efficient in antigenic crosspresentation and priming CD8+ T cells compared to other DC populations (Bachem et al. 2010). Although all DC subsets are able to cross-present antigens in vitro, upon TLR3 stimulation,




CD141+ mDCs remain to be the best cross-presenters of a variety of antigens including necrotic cell-associated antigens (Crozat et al. 2010; Jongbloed et al. 2010; Bachem et al. 2010). The remarkable ability of CD141+ mDCs for cross-presentation of necrotic cell antigens could be explained by high surface expression of CLEC9A, a receptor that specifically bind antigens from dead cells and mediates their cross-presentation (Sancho et al. 2009; Schreibelt et al. 2012). However, cross-presenting properties of CD141+ mDCs were shown to be significantly influenced by various factors including antigen type, DC activation status, tissue location, and inflammatory stimuli (Nierkens et al. 2013). Role of DCs in inflammation: phenotypic plasticity DCs have a certain phenotypic plasticity that could be seen in inflammation. Inflammatory activation was shown to cause phenotypic changes in different DC subsets through stimulation of surface expression of a set of cell markers such as cD11b, CD14, CD16, and CD141 that define phenotype of distinct subsets of myeloid cells in steady-state (Boltjes and van Wijk 2014). Upon inflammatory stimuli, monocytes were shown to differentiate to the so-called inflammatory DCs (iDCs). iDCs in vivo were first observed in mice (Geissmann et al. 2003; Serbina et al. 2003) and recently in humans (Segura and Amigorena 2013). Transcriptome analysis of iDCs showed that this subset shares molecular expression signatures with both mDCs and monocyte/macrophages but has more overlaps with monocytes. For example, human iDCs were found to simultaneously express monocytoid surface markers such as CD14 and CD16 and transcription factors such as ZBTB46 that are essential for DC development (Segura and Amigorena 2013). Like macrophages, CD11c+ CD1c− CD141− iDCs located in human psoriatic lesions produce large amounts of nitric oxide (NO) due to the higher activity of inducible NO synthase (Lowes et al. 2005). In humans, iDCs possess strongly pronflammatory properties because they secrete IL-1␤ and IL-6 and induce differentiation of naïve CD4+ T cells to Th17 cells (Segura et al. 2013). In human pathologies where inflammation plays a central role, the frequency of mDCs subsets is subjected to marked changes. For example in psoriatic skin, dermal CDc141+ mDCs were shown to be reduced while CD1c+ mDCs became elevated compared to the skin of healthy subjects (Zaba et al. 2009). However, numbers of CD1c− iDCs became markedly elevated (by 30-fold). Although both CD1c+ mDCs and CD1c− iDCs contribute to the induction of Th1- and Th17-dependent responses, iDCs seem to be the major players in promoting psoriatic inflammation. Furthermore, CD11c+ CD1c− iDCs were reported to produce a broader repertoire of proinflammatory and proapoptotic molecules including TNFrelated apoptosis-inducing ligand (TRAIL), TLR1, TLR2, and CD32 compared to skin CD1c+ mDCs and therefore could be primarily responsible for increased death of keratinocytes and other skin cells to promote disease progression (Zaba et al. 2010). Regulatory DCs While immune stimulatory properties of mDCs are associated with distinct phenotypic changes, this is less clear for regulatory DCs. Early observations suggested that immune regulatory and tolerogenic function may be a characteristic of immature DCs. Immature DCs were shown to catch, process and present antigens to naïve T cells in the absence of the co-stimulatory signal 2 that result in induction of T cell anergy and deletion (Jonuleit et al. 2000; Lutz et al. 2000). However, recent studies showed that mature DCs with regulatory properties could be detected in variable conditions thereby suggesting that regulatory DCs are a functional state rather than a unique and phenotypically cell subset (Schmidt et al.

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2012). This hypothesis could be supported, for example, by experiments involving a mouse model of inflammatory bowel disease. For intestinal CD103+ DCs, a tolerogenic function was observed in steady state resulting in induction of forkhead box P3 (FoxP3)+ Tregs from naïve CD4+ T cells (Scott et al. 2011). In inflammatory conditions induced by experimental colitis, tolerogenic properties of CD103+ DCs become impaired. Instead of inducing Tregs, DCs exhibited inflammatory properties through production of proinflammatory cytokines and induction of IFN-␥ producing CD4+ T cells (Laffont et al. 2010). Lysteria monocytogenes infection of mice is intensively used as a model to study mechanisms of innate and adaptive immunity. Gut DCs engulf bacteria when then pass through the intestinal barrier and transfer to mesenterical lymph nodes. DCs were shown to be involved in the control of immune response against L. monocytogenes. They allow release of bacteria from phagosomes and replication in cytoplasm in order to process and present bacterial antigens associated with MHC class I to CD8+ cytotoxic T cells (Pamer 2004). Activated CD8+ cytotoxic T cells rapidly destroy invaded bacteria. However, DCs should also control cytoplasmic bacterial replication to prevent DC destruction and further spreading of bacteria. After L. monocytogenes phagocytosis, intestinal DCs quickly maturate and start production of proinflammatory cytokines including IFN-␤, IL-12, and IL-18. They prime differentiation of naïve T cells toward proinflammatory phenotype (Feng et al. 2005). On the other hand, infected DCs were shown to bear immunoregulatory functions through expression of IL-10, a proinflammatory cytokine, and indoleamine 2,3-dioxygenase (IDO), an immunomodulatory protein that suppresses T cell function and mediates host-pathogen relationships (Popov et al. 2006, 2008). The so-called semi-mature DCs that have intermediate features between the immature and mature state were shown to produce low levels of inflammatory cytokines but also possess immunoregulatory properties via induction of Tregs (Lutz 2012). Partial maturation (semi-maturation) of DCs is characterized by up-regulated expression of MHC and costimulatory molecules and lymph node homing capacity but absent (or low-level) production of proinflammatory cytokines. Compared to immature tolerogenic DCs, semi-mature tolerogenic DCs have an advantage because they express homing receptors and are capable to reach T cells at their anatomical locations. Indeed, they should regulate T cells more efficiently than immature DCs. In DCs, partial maturation could be induced by several mechanisms. Inflammatory cytokines such as TNF-␣ and IL-6 were able to induce semi-mature DCs through receptors TNFR1, TNFR2, and IL-6R (Funk et al. 2000; Frick et al. 2010). Pathogens that induce Th2-mediated immune responses such as Leishmania amazonensis, Nippostrongylus brasiliensis, Echinococcus multilocularis, and cholera toxin were shown to cause partial DC maturation (Lutz 2012). Some commensal bacteria such as Bacteroides vulgatus and Lactobacillus rhammnosus could also induce semi-mature DCs (Frick et al. 2006; Müller et al. 2008). Disruption of DC–DC contacts mediated by Ecadherin was found to lead to cell dissociation and semi-maturation through activation of ␤-catenin-Wnt signaling (Van den Bossche et al. 2012). Compared to immature DCs, semi-mature DCs show upregulation of expression of MHC class II and costimulatory molecules such as CD80/B7-1 and CD86/B7-2 but no production of proinflammatory cytokines (Lutz and Schuler 2002). These semimature DCs show up-regulation of expression of MHC class II and costimulatory molecules but no production of proinflammatory cytokines. These cells possess regulatory properties since, when stimulated with myelin antigen, they induce IL-10-producing T regs (so-called Tr1 cells) (Jiang et al. 2007). Similarly, TNF-␣-induced semi-mature DCs after challenge with an antigen become tolerogenic and, when injected to mice with experimentally induced




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autoimmune encephalomyelitis (EAE), promote development of Tr1 cells that diminish EAE-associated inflammation (Menges et al. 2002). Treatment of mouse dermal migratory Ccr7− DCs with low doses of skin antigen was found to induce expression of Ccr7 and semi-maturation of these cells associated with the activation of RelB/p52-dependent transcriptional program. Stimulated semi-mature DCs acquired immunoregulatory properties associated with producting TGF-␤ and priming development of inducible FoxP3+ Tregs in lymph nodes (Chen et al. 2003; Azukizawa et al. 2011). Indeed, microenvironmental conditions could trigger differentiation of mDCs to acquire proinflammatory or regulatory properties. Anti-inflammatory cytokines such as IL-10 and TGF-␤ were shown to induce immunoregulatory functions in DCs. For example, IL-10 suppresses antigen-presenting and immunostimulatory properties of DCs by inhibiting overexpression of MHC class II and CD86 and productin of proinflammatory cytokines IL-12 and TNF-␣ (De Smedt et al. 1997; Pletinckx et al. 2011). TGF-␤ could induce tolerogenic phenotype in DCs through the activation of IDO expression (Belladonna et al. 2008). IDO activation in turn leads to increase in expression of immunoinhibitory molecule programmed cell death protein 1 (PD-1) ligand on the surface of DCs (Wei et al. 2008). Prostaglandin E2 (PGE2 ) could have opposite effects on mDCs depending on the duration and severity of inflammation. In acute inflammation, PGE2 is extensively produced by immune cells, epithelial cells, and fibroblasts and serves as an activator of the proinflammatory response through increasing CCR7 expression on the surface of mDCs and enhancing their migration toward inflamed sites (Legler et al. 2006). However, in chronic and long-term inflammation, PGE2 could stimulate regulatory properties in mDCs by ´ et al. 1997; induction of IL-10 and thrombospondin-1 (Kalinski Doyen et al. 2003). In addition, PGE2 were found to enhance expression of the ␤-chain (p40) of IL-12 but diminishes synthesis of the IL-12 ␣-chain (p35) in DCs. Overall, this results in the reduction of secretion of bioactive IL-12 due to the limited availability of the p40 subunit (von Bergwelt-Baildon et al. 2006).

Myeloid DCs in atherosclerosis Atherosclerotic plaques contain CD11b+ CD11c+ and CD11b− CD11c+ DCs. Normal arteries also contain both types of DCs but population of CD11b− CD11c+ cells is small (Koltsova et al. 2012). In atherosclerosis, CD11b+ CD11c+ subset of DCs was shown to become rapidly increase (Paulson et al. 2010). This subset is likely to arise from monocytes and represent a mixed population of both inflammatory macrophages and DCs (Koltsova et al. 2013). Counts of classical CD11b− CD11c+ DCs including CD11b− CD103+ CD11+ and CD11b− CD8␣+ CD11c+ subsets are also increased in atherosclerotic lesions (Choi et al. 2011; Busch et al. 2014). The role of DCs in atherosclerosis was evaluated in two murine models of atherosclerosis including apolipoprotein E (ApoE)- and low-density lipoprotein receptor mice (Ldlr)-deficient mice, using depletion of DCs with diphtheria toxin (DT). The toxin binds to the DT receptor expressed under control of the CD11c promoter and causes selective depletion of CD11c-positive DCs (Coombes et al. 2007). In ApoE-deficient mice, Gautier et al. (2009) reported depletion of CD11c+ mDCs that was resulted in the development of hypercholesterolemia thereby suggesting for the involvement of DCs. In Ldlr-deficient mice, Paulson et al. (2010) showed that DCs could contribute to the induction of atherogenesis through ingestion of serum lipids. Depletion of CD11c+ DCs caused by single treatment with diphtheria toxin did not influence the plaque size. Multiple injection of the toxin led to the rapid depletion of CD11b− CD11c+ mDCs that highly express CD11c and moderate

decrease of CD11b+ CD11c+ population, which has a modest expression of CD11c. However, toxin-induced depletion of DCs only slightly reduced the lesion size (Paulson et al. 2010). Since CD11c is not a definitive DC cell marker (this marker is shared between murine monocytes, macrophages, and DCs due to the common monocyte-dendritic cell precursor) (Wu et al. 2009; Merad et al. 2013), it is difficult to explain whether these results are specifically interpret the overall proatherogenic role of DCs. Recently, Meredith et al. (2012a) reported construction of a plasmid containing the DT receptor gene under control of the Zbtb46 promoter that specifically regulates commitment and development of mDCs. Probably, injection with this construction should provide obtaining a better quality of data related to the role of mDCs in atherosclerosis. In fact, mDCs serve as a bond that link adaptive and innate immune reactions in atherogenesis. Depletion of factors contributed to the antigen presentation such as CD74, CD80, and CD86 resulted in reduced atherosclerosis (Buono et al. 2004). Koltsova et al. (2012) showed that antigen-presenting cells transfected with a vector expressing yellow fluorescent protein, a cell marker, under the control of the CD11c promoter could efficiently present antigens to T cells and induce production of a proinflammatory cytokine IFN-␥. These data suggest for a rather proinflammatory role of mDCs in atherosclerosis. However, various mDCs subsets play a different role in atherogenesis. In Ldlr-deficient mice, CD103+ CD11c+ cells were shown to play an immune inhibitory role through the mechanism of supporting the homeostasis of FoxP3+ Tregs (Choi et al. 2011). The development of CD103+ CD11c+ mDCs is regulated by FMS-like tyrosine kinase 3 ligand (Flt3L), a growth factor for DCs (Schmid et al. 2010). Consequently, deletion of Flt3L in mice resulted in lack of CD103+ CD11c+ cells and other DC subsets and in advanced atherosclerosis (Choi et al. 2011). Indeed, these findings suggest for the atheroprotective role of CD103+ CD11c+ mDCs. CD8␣+ CD11c+ cells were shown to be also dependent on Flt3L (Hashimoto et al. 2011). Therefore, it is possible that more than one population of DCs could be lacking or functionally disturbed in the absence of Flt3L. Transplantation of myeloid differentiation primarily response gene 88 (Myd88)-deficient CD11c+ DCs to the Ldlr-deficient mouse resulted in reduced stimulation of peripheral effector T cells and diminished accumulation of both effector T cells and Tregs in the plaques (Subramanian et al. 2013). The size of atherosclerotic lesions was increased due to the accumulation of proinflammatory cells of myeloid origin via the mechanism increased plaque monocyte activation associated with the loss of Treg-mediated suppression of chemokine (C–C motif) ligand 2 (CCL2), a secreted factor that is involved in the recruitment of monocytes, effector T cells, and DCs (Luther and Cyster 2001). Therefore, Tlr/Myd88-dependent signaling could be primarily involved to the recruitment of Tregs by regulatory DCs in murine atherosclerosis. Concluding remarks Despite the obvious progress in our knowledge of the development of mDCs, there are still too many gaps in understanding development of human mDCs. Concerning atherosclerosis, it is clear that mDCs contribute to atherogenesis in both ways being involved in supporting proatherogenic arterial inflammation and through suppressing inflammatory responses via induction of selftolerogenic properties and Tregs. The local microenvironment and extrinsic stimuli influence DC phenotype and hence could trigger the phenotypic change toward inflammation or tolerance. However, population of mDCs in atherosclerotic plaques shows significant heterogeneity. In affected humans, different subsets of mDCs are widely uncharacterized. Indeed, the role of each subset of mDCs should be studied in order to better disclose the contribution of each mDC subpopulation in the pathogenesis of atherosclerosis.




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Myeloid cells in cancer-related inflammation.

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Apoptosis: role in myeloid cell development.

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Activation of myeloid dendritic cells, effector cells and regulatory T cells in lichen planus.

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Synovial fluid CD1c+ myeloid dendritic cells – the inflammatory picture emerges.

Human cytomegalovirus tropism for mucosal myeloid dendritic cells.

Thrombin-processed Ecrg4 recruits myeloid cells and induces antitumorigenic inflammation.

Captopril inhibits maturation of dendritic cells and maintains their tolerogenic property in atherosclerotic rats.

Development and function of dendritic cells in health and disease.

Role of SHIP1 in Invariant NKT Cell Development and Functions.

Inflammatory conditions distinctively alter immunological functions of Langerhans-like cells and dendritic cells in vitro.

Intragraft Blood Dendritic Cell Antigen-1-Positive Myeloid Dendritic Cells Increase during BK Polyomavirus-Associated Nephropathy.

Histamine promotes the development of monocyte-derived dendritic cells and reduces tumor growth by targeting the myeloid NADPH oxidase.

Changes in polysialic acid expression on myeloid cells during differentiation and recruitment to sites of inflammation: role in phagocytosis.

The role of dendritic cells in driving genital tract inflammation and HIV transmission risk: are there opportunities to intervene?