Natural and Induced Tolerogenic Dendritic Cells Courtney A

Natural and Induced Tolerogenic Dendritic Cells Courtney A. Iberg and Daniel Hawiger This information is current as J Immunol 2020; 204:733-744; ; of September 28, 2021. doi: 10.4049/jimmunol.1901121 http://www.jimmunol.org/content/204/4/733 Downloaded from References This article cites 203 articles, 76 of which you can access for free at: http://www.jimmunol.org/content/204/4/733.full#ref-list-1

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2020 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Natural and Induced Tolerogenic Dendritic Cells Courtney A. Iberg and Daniel Hawiger Dendritic cells (DCs) are highly susceptible to extrinsic increasing the risk of autoimmune responses against self- signals that modify the functions of these crucial APCs. antigens (2, 4–7). Maturation of DCs induced by diverse proinflamma- The priming of self-reactive peripheral T cells is controlled tory conditions promotes immune responses, but cer- by tTreg cells (8). However, the functions of tTreg cells tain signals also induce tolerogenic functions in DCs. may be overwhelmed by specific proinflammatory auto- These “induced tolerogenic DCs” help to moderate immune activation; also, in some individuals, the devel- immune responses such as those to commensals present opment of tTreg cells may be compromised (2, 4, 9, 10). at specific anatomical locations. However, also under Various animal models of autoimmune diseases initiated in healthy animals after immunization with specific self-antigens steady-state conditions, some DCs are characterized Downloaded from by inherent tolerogenic properties. The immunomod- either in the presence of adjuvants or in the context of an ulatory mechanisms constitutively present in such introduced infectious agent have demonstrated that specific priming of preexisting self-reactive T cells mediates an auto- “natural tolerogenic DCs” help to promote tolerance immune process (2, 4–7). Therefore, pathways of thymic to peripheral Ags. By extending tolerance initially tolerance need to be extended by the specific mechanisms established in the thymus, these functions of DCs operating in the peripheral immune system. Particularly, au- help to regulate autoimmune and other immune re- toimmune responses can be ameliorated or even completely http://www.jimmunol.org/ sponses. In this review we will discuss the mechanisms prevented by the Ag-specific, peripherally formed Treg (pTreg) and functions of natural and induced tolerogenic DCs cells that are induced extrathymically by DCs (7, 11). and offer further insight into how their possible manipulations may ultimately lead to more precise treat- Dendritic cells in peripheral tolerance ments for various immune-mediated conditions and diseases. The Journal of Immunology, 2020, 204: The roles of DCs in peripheral tolerance have been established 733–744. by multiple lines of independent experimental evidence. The

disturbance of tolerance and immune homeostasis caused by by guest on September 28, 2021 the absence of DCs and their subsets was observed in various endritic cells (DCs) are APCs critical for the initi- experimental systems that relied on a specific in vivo killing of ation of T cell immune responses and for the gov- DCs expressing diphtheria toxin receptor or diphtheria toxoid D erning of immune tolerance. Together with other A subunit or by other means, such as a chemical depletion of types of cells in the thymus, DCs have important roles in DCs (12–16). These results are in agreement with other early mediating central tolerance, combining thymic deletion studies that identified the roles of DCs in the induction of of self-reactive T cells and a production of thymically de- peripheral tolerance by employing methods of specific deliv- rived regulatory T (tTreg) cells in a cumulative process aimed ery of defined Ags to DCs in vivo, tracking the uptake of at preventing overt anti-self responses (1). However, because proteins to DCs, and the transgenic expression of ectopic Ags of differing efficiencies of antigenic presentation in the as cytosolic proteins in DCs (17–20). The combination of thymus and the periphery, and cross-reactivity of TCRs, specific Ag-targeting methods with various genetic models the mature peripheral T cell repertoire still contains T cells of DCs has allowed for further advances in our understanding that may be reactive to self (2, 3). These self-reactive pe- of the importance of DCs in governing peripheral tolerance, ripheral T cells can then be primed in the periphery, even as we also recently discussed in Ref. 11. by low-affinity peptides that are below their original thresh- The specific functions of DCs depend, in part, on the de- olds for negative selection in the thymus (2, 4), ultimately velopmentally determined diversity of DC subsets reviewed

Department of Molecular Microbiology and Immunology, Saint Louis University conventional DC; DC, dendritic cell; DC-SIGN, DC-specific ICAM-3–grabbing School of Medicine, St. Louis, MO 63104 nonintegrin; EAE, experimental autoimmune encephalomyelitis; HVEM, herpesvirus entry mediator; itDC, induced tolerogenic DC; LN, lymph node; MHCII, Received for publication September 16, 2019. Accepted for publication October 4, MHC class II; moDC, monocyte-derived DC; MS, multiple sclerosis; mTOR, 2019. mammalian target of rapamycin; ntDC, natural tolerogenic DC; PD-1, pro- This work was supported in part by National Institute of Allergy and Infectious Diseases/ grammed death-1; pDC, plasmacytoid DC; PD-L1, programmed death ligand-1; National Institutes of Health Grant R01AI113903 (to D.H.). PRR, pattern recognition receptor; pTreg,peripherallyformedTreg;RA,retinoic acid;Treg,regulatoryT;tTreg,thymicallyderivedregulatoryT;VDR,vitaminD Address correspondence and reprint requests to Dr. Daniel Hawiger, Department of receptor. Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Doisy Research Center, 1100 South Grand Boulevard, Room 715, St. Louis, MO Ó 63104. E-mail address: [email protected] Copyright 2020 by The American Association of Immunologists, Inc. 0022-1767/20/$37.50 Abbreviations used in this article: AHR, aryl hydrocarbon receptor; BMDC, bone marrow–derived DC; BTLA, B and T lymphocyte associated; cDC, www.jimmunol.org/cgi/doi/10.4049/jimmunol.1901121 734 BRIEF REVIEWS: NATURAL AND INDUCED TOLEROGENIC DENDRITIC CELLS extensively by Murphy and colleagues (21) and Merad et al. promote in T cells various mechanisms of tolerance, including (22). Both human and murine DCs consist of two main T cell anergy, T cell deletion, and a conversion of pTreg cells populations, conventional DC (cDC) and plasmacytoid DC (11). We therefore propose to refer to such DCs as “natural (pDC), both of which develop from progenitors in the bone tolerogenic DCs” (ntDCs) (Fig. 1). marrow and then differentiate into various subsets present throughout multiple tissues (23, 24). The cDC population Establishing peripheral tolerance by natural tolerogenic functions can be further divided into the DC1 and DC2 subsets, as of DCs defined by the transcription factors required for their devel- The physiological steady state can be defined by the undis- opment. The DC1 subset, which requires the transcription turbed expression of cytokines and other molecules contrib- factors Irf8, Id2, and Batf3 for development, is distinguished uting to the baseline conditions that, together with stromal by the expression of XCR1 and further characterized by the cells of the secondary lymphoid tissues, provide a framework expression of additional cell surface molecules, including B for the interactions between DCs and T cells (35, 36). Initially, and T lymphocyte associated (BTLA), CD8a, and DEC-205. it was postulated that, in the steady state, DCs remain im- In contrast, the development of DC2s is governed by the mature akin to BMDCs or moDCs that are characterized by transcription factors Irf4 and Notch2, and these DCs are lower expression of MHC and costimulatory molecules when distinguished by cell surface expression of CD172a (SIRPa) cultured in the absence of maturation signals (35). However, as well as DCIR2 and CD11b (11, 23, 24). Although not a the available experimental evidence has clearly shown that, main focus of this review, pDCs, characterized by the ex- even in the steady state, DCs can constitutively initiate ac- Downloaded from pression of cell surface molecules (including B220, bone tive mechanisms of tolerance in T cells, such as the conversion marrow stromal Ag 2 [BST2], and Siglec-H), are primarily of pTreg cells (7, 11). These general contradictions were involved in antiviral responses but also have some roles in recognized early by Lutz and Schuler, who proposed that + + + tolerance (11, 25). Importantly, CD141 (BDCA-3 ) XCR1 the division between “immature DCs” and “mature DCs” + + + + BTLA human DC1s and CD1c CD172a CD11b human (as defined by DC phenotypes) did not necessarily correspond DC2s share many developmental, phenotypical, and func- with “tolerogenic DCs” and “immunogenic DCs,” respec- http://www.jimmunol.org/ tional similarities with their murine counterparts (21, 26). tively. Instead, divisive tolerogenic and immunogenic matu- In addition to their roles in tolerance, DCs have crucial ration processes were proposed (31), further supported by the functions in the initiation of immune responses. The efficient identification of transcriptional determinants of certain tol- priming of immune responses by specific DC subsets requires erogenic and immunogenic maturation states in DCs as well additional signals from the proinflammatory environment that as by the emerging concept of “homeostatic maturation” of can be sensed through specific pattern recognition receptors DCs under steady-state conditions (37–40). For example, a (PRRs) (27–29). These signals lead to the DC acquisition decrease in E-cadherin–mediated cell–to–cell contact results of enhanced properties to induce immune responses in a proin specific increases in expression of MHC class II (MHCII) by guest on September 28, 2021 cess referred to as maturation. Overall, the model of such and costimulatory molecules (39). The concept of DC mat- proimmunogenic DC maturation postulates increased proin- uration in the steady state was additionally defined by other flammatory cytokine production and increased cell surface observations of multiple specific gene expression changes expression of costimulatory and MHC molecules and che- comparable, in scope, to those observed under TLR agonist– mokine ligands or receptors in response to microbial and mediated maturation (30). This process of maturation under other proinflammatory stimulation (28, 30). In addition to homeostatic conditions has also been proposed to result in this maturation process resulting in increased immune re- functions of DCs necessary to induce active mechanisms of sponses, specific extrinsic signals were also proposed to induce tolerance (38). Although the specific mechanisms governing tolerogenic differentiation of DCs. The experiments using DC functions in vivo under steady-state conditions following bone marrow–derived DCs (BMDCs), monocyte-derived their initial development from the bone marrow precursors are DCs (moDCs), and DCs obtained ex vivo showed that still being uncovered, it is clear that these processes are con- some PRR agonists, as well as various other physiological and tinuous, and some possibly cell autonomous, resulting in the pharmaceutical agents, can allow for the induction of DCs stable numbers and phenotypes of DCs expressing crucial with tolerogenic functions. Further, the experiments in vivo molecules involved in tolerance (Fig. 2 and as discussed below). revealed that, in response to certain signals in specific ana- In the steady state, DCs can induce multiple mechanisms of tomical sites (including the intestines and airways), some tolerance in T cells including anergy, but a de novo conversion DCs help to maintain immune homeostasis toward com- of pTreg cells bestows a dominant and long-lasting tolerance to mensal organisms and other Ags, even under partially peripheral Ags (7, 11, 41–44). Although in the steady state proimmunogenic conditions (28, 31–33). We propose to Ags initially acquired by all cDCs can induce tolerance, DC1s refer to such DCs that acquire tolerogenic properties ei- are more prone to induce tolerogenic effects as compared with ther in vitro or in vivo as “induced tolerogenic DCs” (itDCs), DC2s (7, 11, 42). The specialization among DCs can be at- as partially based on the terminology first introduced by tributed to different localization of DCs within a local ar- Maldonado and von Andrian (34). chitecture of immune organs, differences in the efficiencies However, even in the absence of specific extrinsic signals, of processing and presentation of Ags to T cells, and the generally referred to as steady-state conditions, many DCs that specific immunomodulatory mechanisms in DC1s and DC2s are present in the spleen and other lymphoid organs do not (11, 45–48). The immunomodulatory pathways are of par- necessarily remain as “immature” immunological bystanders ticular importance in the mediation of a tolerogenic part- but instead have important roles in initiating and maintaining nership of DCs and T cells (49). Importantly, the engagement tolerance to available peripheral Ags (11). These DCs inherently of immunomodulatory axes (including programmed death The Journal of Immunology 735

FIGURE 1. The role of ntDCs and itDCs in extrathymic tolerance. Peripheral tolerance extends tolerance initiated centrally in thymus. The ntDCs and itDCs function to promote the deletion or anergy of self-reactive T cells as well as to induce pTreg cells. ntDCs are generally tissue-resident DCs found in multiple immune organs, including the spleen and LNs (highlighted in blue). itDCs are generally found

in various tissues and organs, including the lungs, the Downloaded from intestines, and the skin (highlighted in yellow). In these locations, itDCs are in constant contact with a variety of environmental stimuli provided by commensal and pathogenic organisms. http://www.jimmunol.org/ by guest on September 28, 2021 ligand-1 [PD-L1]/programmed death-1 [PD-1], CD80/CD86/ protolerogenic cytokine (34, 49, 59, 60). By acting directly CTLA-4, and B7h/ICOS) can promote Foxp3 expression, on T cells, TGF-b promotes differentiation of both Treg pTreg cell induction, and tolerance (7, 11, 49). Specifically, the and some effector T cells (43, 61–65). Metabolites, such as PD-L1/PD-1 axis promotes immune tolerance via PD-L1’s retinoic acid (RA), enhance tolerogenic properties of cy- competition with costimulatory CD28 for binding with tokines including TGF-b, further promoting the induction B7-1 as well as by the recruitment of SHP-2 by PD-1, of Foxp3 expression and the amelioration of autoimmune which negatively impacts TCR signaling (50). Moreover, disease (66–70). CTLA-4 (CD152) expressed on the T cell surface competes In addition to the immunomodulatory pathways described with the costimulatory molecule CD28 for binding with above, which can directly contribute to inducing Foxp3 ex- CD80/CD86 (B7-1 and B7-2) present on the surface of pression in pTreg cells, recent results identified the roles of the DC. Although CTLA-4 can remove CD80/CD86 from BTLA and CD5 in promoting pTreg cell homeostasis via the the DC surface, it also directly negatively regulates CD4+ modulation of the sensitivity of the developing pTreg cells to and CD8+ T cell activation by dampening TCR signaling, effector-differentiating cytokines (7, 42, 71, 72). Among the hindering IL-2 production, and preventing cell cycle pro- DC populations, BTLA is expressed specifically in DC1s (72). gression (51–53). Finally, B7h (ICOS-L or B7RP-1) is During the interactions between the BTLAhi DC1s and constitutively expressed on DCs, and expression of its re- T cells in the steady state, BTLA signals through herpesvirus ceptor, ICOS, is induced upon T cell activation (49). Re- entry mediator (HVEM) in naive CD4+ T cells to activate lated to other members of the CD28 Ig superfamily, ICOS MEK and, subsequently, the transcription factor ETS1 to (together with its binding partner B7h) has proven impor- increase expression of Cd5 (42, 72). High CD5 expression tant in the development of Treg cells, and a deficiency in then allows for a conversion of these T cells to Foxp3+ pTreg ICOS signaling has rendered mice more susceptible to cells by interfering with mammalian target of rapamycin various autoimmune pathologies, although ICOS functions (mTOR) activation in response to effector-differentiating are required for the progression of some autoimmune processes cytokines, such as IL-4, IL-6, and IFN-g (7, 42, 71). (54–58). BTLAhi DC1s reside in lymphoid organs, including the Among various cytokines governing immune responses, the spleen, and these resident lymphoid tissue DCs are ideally presence of TGF-b is often correlated with maintaining im- positioned to capture systemic self-antigens, including those mune homeostasis. The absence of TGF-b leads to sponta- derived from apoptotic cells (20, 73, 74). Although the neous lymphoproliferation and inflammatory disease, and specific roles of BTLA in governing tolerance among CD8+ TGF-b also influences the expression of IL-10, an important T cells remain unclear, DC1s can maintain tolerance to 736 BRIEF REVIEWS: NATURAL AND INDUCED TOLEROGENIC DENDRITIC CELLS Downloaded from http://www.jimmunol.org/ FIGURE 2. ntDCs promote tolerance in the steady state. Using multiple receptors (examples of which are shown), ntDCs constitutively uptake and process tissue-derived Ags from apoptotic cells for subsequent presentation to T cells, thereby further enhancing tolerance toward self-antigens. Similarly, ntDCs uptake, process, and present soluble Ag. ntDCs, which are predominantly DC1s, inherently express immunomodulatory molecules (including BTLA, PD-L1, B7h, and CD80/CD86) as well as cytokines (such as TGF-b and IL-10). Interaction of BTLA with the T cell–expressed receptor HVEM is necessary for the efficient induction of pTreg cells and long-lasting tolerance. self-antigens by presenting endogenous Ags to both CD4+ (87, 88). However, under steady-state conditions, the resident + hi and CD8 T cells (73, 75). DC1s also have important roles lymphoid tissue BTLA DC1s (as well as some migratory by guest on September 28, 2021 in eliciting Th1 responses as well as in cross-priming CD8+ DCs) exhibit inherent tolerogenic properties (11). The ability cytotoxic T cells (23). Such versatile functions of some of DC1s to uptake, process, and present Ags to T cells in the DC1s may reflect complex mechanisms mediated by BTLA steady state has been demonstrated by using multiple meth- and HVEM (76–79), yet it is also interesting to speculate ods, including a direct targeting of Ags to such DCs by using that at least some of these proimmune functions may be chimeric Abs specific for DEC-205 and other surface recep- performed by DC1s characterized by low expression of tors (11, 17, 89). Importantly, the combination of genetic BTLA. models including a DC-specific deletion of Irf4 (resulting in Nevertheless, it is clear that apoptotic materials are an an increased DC1/DC2 ratio) or a deletion of Batf3 (resulting abundant source of tissue self-antigens crucial for the main- in decreased numbers of DC1s) and targeted Ag delivery to tenance of immune tolerance (20, 80, 81). The relationship DC-specific molecules has helped to further clarify the between the uptake, processing, and presentation of apoptotic specific functions of DC subsets (11, 17, 42, 49). materials and the functional characteristics of DCs is complex. In addition to the tolerance promoted by resident lymphoid The phagocytic scavenger receptor CD36 has long been rec- tissue DCs, tolerance to self-antigens is also promoted by ognized for its role in facilitating the uptake of apoptotic migratory DCs that transport Ags from the nonlymphoid materials via recognition of phosphatidylserine found on the tissue to the lymph nodes (LNs). Such migratory DC1s, es- outer leaflets of the membranes of apoptotic cells (74, 82). pecially those found in skin and parenchymal organs, undergo Consistent with the notion that DC1s are primarily respon- homeostatic maturation in the steady state and have tolero- sible for the constitutive uptake of apoptotic materials, CD36 genic functions (40, 90–92). However, the tolerogenic func- is expressed highly on DC1s compared with DC2s and pDCs tions of many migratory DCs are also induced at certain (83, 84). In addition to being a source of Ags, an exposure to anatomical locations (such as the intestines) upon exposure to apoptotic materials may also enhance the tolerogenic prop- specific extrinsic stimuli (as discussed below). erties of some DCs. An engagement of CD36 can inhibit maturation of moDCs induced by proimmunogenic stimuli Inducing tolerogenic DCs for the maintenance of homeostasis and can induce tolerogenic BMDCs that resist LPS stimula- In contrast to resident lymphoid tissue DCs and DCs mi- tion and induce Foxp3+ pTreg cell development (85, 86), also grating from the parenchymal organs in the steady state, many discussed later in the text. DCs that are exposed to various environmental stimuli present In contrast, necrotic-type materials derived from injured cells in the intestines, airways, and skin are constantly at risk for can be recognized by Clec9a (DNGR-1), a C-type lectin expressed undergoing immunogenic maturation. However, as discussed by some DC1s, resulting in inflammation and maturation of DCs earlier in the text, these DCs do not induce detrimental The Journal of Immunology 737 immune responses and instead induce tolerogenic functions. production, whereas stimulation of TLR-4 promotes Th17- The specific tolerogenic mechanisms employed by itDCs re- and IL-17–driven pathology (119). Various TLRs may also main an area of active investigation, but it is clear that, despite physically associate as heterodimers to promote contrasting the presence of proinflammatory mediators, these DCs are responses depending on the specific composition of each typically characterized by an elevated production of various heterodimer. Studies using the Yersinia pestis virulence factor anti-inflammatory cytokines and other regulatory molecules LcrV showed that recognition of LcrV by a TLR-2/TLR-6 (11, 93–99). heterodimer could lead to itDC induction, complete with Among such specific anatomical sites, the skin represents a IL-10 production and Tr1 induction, whereas recognition crucial barrier that is in constant contact with foreign Ags and of LcrV by a TLR-2/TLR-1 heterodimer resulted in IL-12 commensal microbes and that requires intricately regulated production and induction of effector Th1 cells (120). immune responses orchestrated by DCs (93, 100). The lungs A particular agonist may also lead to divergent immune are another crucial anatomical site that is continually exposed responses by stimulating different PRRs. Early reports sug- to commensals and pathogens, therefore also requiring active gested that zymosan, a glucan derived from yeast cell walls, immunoregulation. Correspondingly, DCs obtained from promotes IL-10 production and tolerance by concomitant patients with chronic obstructive pulmonary disease were engagement of TLR-2 and dectin-1 (121). However, later shown to produce IL-10, leading to the induction of Tr1 reports from ex vivo and in vivo experimental systems sug- regulatory cells (95, 101, 102). The intestines are yet an- gested that divergent responses may arise from zymosan’s other key organ that remains in constant contact with a large stimulation of these PRRs. It was found that TLR-2 ligation Downloaded from number of commensal bacteria and that can also be exposed by zymosan increases the expression of Raldh2 by DCs, to potentially pathogenic microbes. Oral administration of leading to the production of RA and the eventual promotion Ags is well established to lead to the induction of Foxp3+ Treg of Treg cells via the suppression of effector differentiation. In cells, thereby helping to maintain homeostasis (103). contrast, ligation of dectin-1 increases Th1 and Th17 differ- It has recently been suggested that the specific anatomical entiation and exacerbates autoimmunity (116). In some in- organization of gut-draining LNs may play a role in the balance stances, the concomitant signaling of specific combinations of http://www.jimmunol.org/ of tolerance and immunity, as proximal and distal gut-draining other PRRs (such as TLR-2 and TLR-4 or TLR-3, -4, or -5 LNs supported primarily tolerogenic and immunogenic re- and DC-SIGN) may result in tolerogenic profiles, including sponses, respectively (47). In addition to such anatomic spe- increased IL-10 production and lower costimulatory molecule cialization, other studies have demonstrated that the presence expression by DCs (122, 123). of commensal microbes from the human gut, dietary me- In addition to TLRs, signaling via G-protein–coupled tabolites, and some other biologically active molecules results receptors (such as GPR109a and GPR81) extends DC- in the formation of itDCs that can differentiate Foxp3+ Treg mediated tolerance in the gut. The G-protein–coupled

cells and regulatory Tr1 cells and decrease the numbers of receptor GPR109a is a receptor for commensal bacteria– by guest on September 28, 2021 effector T cells (33, 104–107). Accordingly, the pTreg cell– produced butyrate and niacin that induce production of IL-10 2 inducing functions of Irf8/Batf3-dependent CD103+CD11b and Aldh1a1 in DCs (124). The deficiency of GPR109a 2 2 DC1s help maintain a local immune homeostasis within the (genetically modeled in Niacr1 / mice) results in an in- gut-associated lymphoid tissues as well as at other mucosal creased susceptibility to colonic inflammation and colon surfaces and also some immune-privileged sites, such as the cancer in azoxymethane- and dextran sulfate sodium–treated eye (12, 13, 32, 108–110). Although DC2s are generally less mice, respectively (124). Similarly, the G-protein–coupled efficient at inducing pTreg cells, some itDC2s in the intes- receptor GPR81 is expressed in intestinal DCs and macro- tines still promote both Treg cell–independent and Treg cell– phages and has been shown to be activated by lactate, a dependent tolerance (111, 112). product of microbial fermentation that is present in abun- Recent work identified that stimulation through certain danceinthecolon(125,126).Thegeneticdeletionof PRRs and the presence of specific cytokines and metabolites GPR81 results in a decrease in tolerance protecting from can actively divert DCs toward tolerogenic functions [(34, 47, colitis, as evidenced by an increase in proinflammatory cy- 93, 101, 113) and (Fig. 3)]. In contrast to their proimmu- tokine production, a decrease in regulatory factors such as nogenic roles, some PRRs may contribute to a tolerogenic IL-10, and a decrease in IDO1 expression; correspondingly, sensitization (29, 33, 114–117). However, the impact of in- pharmacological activation of GPR81 has been shown to dividual PRRs on the induction of tolerogenic DCs is likely to lessen murine colitis severity (126). Also, other molecules, be context dependent. For example, BMDCs differentiated in such as DC-SIGN, play a specific role in itDC induction, as the presence of splenic stroma were found to produce high well as in the induction of tolerogenic functions in macro- amounts of IL-10 and dampen naive CD4+ T cell responses in phages, by promoting specific mechanisms of tolerance (such culture (36). Paradoxically, an additional stimulation with as the production of IL-10) in response to various microor- TLR-2, -3, -4, and -9 agonists of DCs cocultured with splenic ganisms (117, 127, 128). However, the binding of DC-SIGN stromal cells further enhances their tolerogenic state, resulting (possibly in concert with the binding of TLRs) to various in heightened production and secretion of CXCR3 chemo- ligands, including cell wall components and modified oligo- kine IFN-g–inducible protein 10 (IP-10) and a correspond- saccharides derived from bacterial LPS, results in divergent ing decrease in Th1 proliferation (118). Nevertheless, certain tolerogenic or immunogenic DC–mediated immune re- TLRs such as TLR-2 appear to be more tolerogenic than sponses and may also lead to Th1 responses (122, 129–131). other TLRs. In a murine disease model of arthritis, the mi- Certain cytokines and metabolites have crucial roles in in- crobial commensals’ stimulation of TLR-2 on APCs producing and governing the functions of itDCs as well as in motes Treg cell suppressive functions and dampens IFN-g shaping the responses of DCs to PRR ligands. For example, the 738 BRIEF REVIEWS: NATURAL AND INDUCED TOLEROGENIC DENDRITIC CELLS Downloaded from

FIGURE 3. itDCs promote T cell tolerance in response to exogenous signals. itDCs can be induced by multiple types of molecules, including microbial components (which bind to various PRRs, such as TLR-2), pharmacological and dietary agents (such as corticosteroids and probiotics) or certain physiological agents that bind to the AHR or the VDR, and also by other specific metabolites, cytokines, and growth factors. The downstream diverse immunoregulatory effects are mediated by several different signaling pathways, including NF-kB, Wnt/b-catenin, and mTOR, ultimately resulting in active mechanisms of tolerance that induce the expression and production of multiple immunomodulatory mediators, including IL-10, RA, and kynurenine (Kyn) (a metabolic product of tryptophan http://www.jimmunol.org/ catabolism that is mediated by IDO1). addition of IL-10 to human DC cultures may lead to decreased signaling directly affected DCs and subsequent T cell re- expression of MHCII (HLA-DR) and costimulatory mole- sponses. A more recent report highlighted the role of IL-27 cules, resulting in T cell anergy (132, 133). In the small in- and the immunoregulatory molecule CD39 expressed by testine, RA is locally found at high concentrations due to the DCs. Specifically, CD39, whose expression is induced by metabolism of dietary vitamin A (109, 134). This localized IL-27, reduced NLRP3 inflammasome activation in DCs, presence of RA then promotes the expression of Raldh2 and thereby reducing subsequent Th1 and Th17 effector T cell by guest on September 28, 2021 production of additional RA by CD103+ DCs in the lamina differentiation (146). propria, ultimately resulting in the increased induction of Other extensively studied physiological factors that function IL-10–producing Foxp3+ Treg cells (as well as in the inhibi- in itDC promotion are ligands for the aryl hydrocarbon re- tion of TGF-b–mediated Th17 cell induction and in the ceptor (AHR), which is important in the regulation of the imprinting of gut-homing receptors on T cells) (66, 108, 109, balance between the formation of regulatory and effector 135–137). Consistent with its protolerogenic roles, IL-10 can T cells (147). The endogenous ligands of AHR, such as then downregulate DC expression of MHCII and costimu- 2-(19H-indole-39-carbonyl)-thiazole-4-carboxylic acid methyl latory molecules and reverse the effects of proinflammatory ester (ITE), also act directly on DCs by skewing them toward cytokines, such as IL-6 and TNF-a (60). Further, IL-10 a tolerogenic profile characterized by decreased production treatment of human DCs upregulates TLR-2 expression in of inflammatory cytokines like IL-6 and IL-12 and in- response to LPS administration, consistent with the pro- creased production of suppressive TGF-b and IL-10 (104, tolerogenic functions observed following TLR-2 activation 148). In DCs, AHR can induce expression of IDO1, an (as discussed above). Such treated DCs also decrease ex- immunosuppressive enzyme that catabolizes tryptophan into pression of IL-12–related cytokines, possibly further indi- kynurenine (Kyn) and other metabolites (148). Further, the cating collaborative roles of IL-10 and TLR-2 in the upregulation of IDO1 and Socs2 expression and increased RA dampening of the immune response (138). production by DCs contribute to a decrease in the proin- In addition to IL-10, the IL-12 cytokine family member flammatory cytokine milieu and the subsequent induction IL-35, predominantly produced by Treg cells, was proposed to of Foxp3+ Treg cells (149). Together, these findings indicate dampen T cell responses (139). Similarly, IL-37 decreases the a crucial role of ITE and AHR signaling in the induction of production of proinflammatory cytokines induced by LPS itDCs that could have therapeutic roles in multiple types of stimulation, and the forced expression of IL-37b in murine autoimmune responses (150). skin DCs promotes tolerogenic DC induction, thereby af- Vitamin D3 represents another key physiological factor fecting contact hypersensitivity challenge (140, 141). Among that may induce tolerogenic DCs (151–153). The active form other cytokines, IL-27 was initially considered to be proim- of vitamin D3 induces immunoregulatory properties upon munogenic (142). However, other studies indicated the role binding to the vitamin D receptor (VDR), which is selec- of IL-27 in suppressing the differentiation of effector T cells tively expressed by various cell types, including intestinal and in autoimmune models, such as experimental autoimmune skin epithelial cells, osteoblasts, CD4+ and CD8+ T cells, encephalomyelitis (EAE), an animal model of multiple scle- and also multiple APCs, including macrophages, monocytes, rosis (MS) (143–145). Still, it remained unknown how IL-27 and DCs (151, 154). VDR agonists increase IL-10 production The Journal of Immunology 739 but decrease expression of IL-12 and CD80/CD86 and CD40 relevant for transplantations as well as tumor immunology by DCs (155). Additionally, itDCs induced by VDR agonists, (11). Both ntDCs and itDCs are relevant for such therapeutic such as calcitriol and paricalcitol, are poor inducers of Ag- manipulations, and the targeted delivery of Ags to DEC-205+ specific effector T cells but are potent inducers of Treg cells and other DCs has proven to be a powerful way to reinforce (151–153, 156). It was further demonstrated that DCs may tolerance to self-antigens implicated in the autoimmune also synthesize the active form of vitamin D3, therefore process (89). For example, the spontaneous induction of pe- providing a local source of this crucial immunomodulant, ripheral tolerance in response to Ags derived from organs altering immune cell trafficking, and further increasing the insulated from the immune system (such as the CNS), is DC secretion of the chemokine CCL22, which attracts Treg likely less efficient (7, 11). This results in an increased po- cells (157–161). Overall, VDR agonists are promising ther- tential for autoimmune diseases such as in animal models of apeutics for autoimmune diseases, transplantation tolerance, MS, which can be readily provoked after an immunization of and allergies (151–153, 156). healthy animals with CNS Ags (7, 178, 179). However, such Other physiological factors may also play a role in itDC autoimmune responses can be blocked by tolerance induced promotion. Vasoactive intestinal peptide decreases production by targeted delivery of various tissue-specific Ags to DCs, of proinflammatory TNF-a and IL-6 and increases produc- allowing for efficient Ag presentation to self-reactive T cells tion of IL-10 in human DCs despite a pre-exposure to LPS, (11, 17, 18, 89). thereby mediating T cell anergy (162). Also, an addition of In these initial experiments, DCs were targeted in vivo with seminal plasma to differentiating moDCs yielded high regu- anti–DEC-205 chimeric Ab to deliver a potentially enceph- Downloaded from latory cytokine and low proinflammatory cytokine production alitogenic peptide Ag derived from myelin oligodendrocyte profiles in such moDCs (163). glycoprotein, which was genetically fused to the Ab molecule, In addition to these physiological factors, 14-dehydroergosterol to prevent subsequently induced EAE (18). These early results (14-DHE), an ergosterol analogue–based compound derived were then extended to other EAE models and various en- from fermented wheat bran, induces tolerogenic properties in cephalitogenic Ags that were delivered through DC-specific

DCs, although the exact mechanisms are unclear (164, 165). molecules, as recently reviewed in Refs. 11 and 89. The targeting http://www.jimmunol.org/ Similarly, multiple pharmacological agents, including chem- of Ags to DCs has also been successful in mediating tolerance ically modified TLR ligands, JAK inhibitors, corticosteroids, in multiple different models of autoimmunity, including dia- cisplatin, antibiotics, probiotics (including bacterial species of betes, colitis, and arthritis, as well as in a model of graft-versus- the Lactobacillus, Bifidobacterium, and Streptococcus genera), host disease (180–183). Overall, this specific delivery of Ags and dietary supplements (such as zinc) have been shown to results in tolerogenic mechanisms that prevent autoimmunity. promote tolerogenic profiles in BMDCs and moDCs. These In addition to the delivery of Ags specifically targeted to profiles are characterized by changes at both the transcrip- DCs, other studies found that certain formulations of Ags

tional and translational levels, ultimately leading to decreased (such as nanoparticles or specifically modified cellular material) by guest on September 28, 2021 production of the inflammatory cytokines TNF-a and IL-6, could lead to their in vivo acquisition by DCs and to the decreased expression of costimulatory molecules, increased amelioration of autoimmune processes including EAE and expression of coinhibitory molecules like PD-L1, and the diabetes (184–187). Despite generally lacking cell target production of the anti-inflammatory cytokines IL-10 and specificity, these methods showed promise in the treatment of TGF-b (166–169). ongoing autoimmune processes, particularly when addition- Among the intrinsic signaling pathways involved in sensing ally coupled with agents known to induce the formation of specific extrinsic factors that induce tolerogenic properties in itDCs under proinflammatory conditions (149). Some of DCs, Wnt/b-catenin is a major molecular pathway involved those methods also incorporated DC-specific Abs to en- in the promotion of itDCs and the increased production of hance the specificity of the delivery system (188), although anti-inflammatory cytokines (such as TGF-b, RA, and IL-10) most of such Ab-coupled immunogenic particles have been and, conversely, in blocking the production of NF-kB– tested for new vaccine approaches (189). In addition to induced proinflammatory cytokines (32, 33, 67, 170). De- controlling autoimmunity, DC-mediated tolerance holds ficiencies in Wnt receptors LRP5/6 and b-catenin–signaling promise in mitigating transplant rejection (as recently mechanisms enhance proinflammatory cytokine production reviewed by Thomson et al. in Ref. 190). Importantly, DCs and Th1/Th17 effector responses and increase disease severity can cooperate with other types of immune cells, such as in mouse models including colitis and MS (67, 171–174). NKTcells,topreventgraftrejections(191). Noncanonical Wnt signaling mediated by Wnt5a is also in- In human systems, the most available options thus far have volved in the promotion of tolerance by modifying DC been to induce itDCs ex vivo, analogous to the induction of maturation and IL-10 production in response to TLR agonists itDCs from murine BMDCs, and to subsequently treat them (175). In addition to Wnt/b-catenin, mTOR emerges as an with agents that can potentially further promote such itDC important regulator of DC functions that may also affect differentiation in vivo. Either murine BMDCs or moDCs tolerogenic mechanisms (176, 177). derived from humans afflicted with an autoimmune disease were treated in vitro with the pharmacologic agents PEGylated–TLR- Harnessing the tolerogenic functions of DCs for 7 ligand, dexamethasone plus monophosphoryl lipid A, therapeutic applications tofacitinib, or prednisolone and were then used to delay dis- ThefunctionsofDCsasinducersoftolerancerepresent ease onset or ameliorate disease severity in diabetes, rheuma- important therapeutic opportunities. Modulation of such DC- toid arthritis, EAE, and myasthenia gravis, respectively (166, induced tolerance can help block different forms of autoim- 167, 169, 192–194). Also, treatment with IL-10 leads to the munity and also impact other types of immune responses formation of itDCs that likely possess clinical relevance (195). 740 BRIEF REVIEWS: NATURAL AND INDUCED TOLEROGENIC DENDRITIC CELLS

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