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. Author manuscript; available in PMC: 2016 Apr 1.
Published in final edited form as: Discov Med. 2015 Apr;19(105):303–310.

Wnt Signaling in Dendritic Cells: Its Role in Regulation of Immunity and Tolerance

Daniel Swafford 1, Santhakumar Manicassamy 1,2
PMCID: PMC4513356  NIHMSID: NIHMS696630  PMID: 25977193

Abstract

A fundamental puzzle in immunology is how the immune system launches robust immunity against pathogens while maintaining a state of tolerance to the body's own tissues and the trillions of commensal microorganisms and food antigens that confront them every day. Innate immune cells, such as dendritic cells (DCs) and macrophages, play a fundamental role in this process. Emerging studies have highlighted that the Wnt signaling pathway, particularly in DCs, plays a major role in regulating tolerance versus immunity. Here, we review our current understanding of how Wnt-signaling shapes the immune response and, in addition, highlight unanswered questions, the solution of which will be imperative in the rational exploitation of this pathway in vaccine design and immune therapy.

Introduction

A central problem regarding diseases arising from aberrations in immune regulation primarily concerns the diametric nature of the functions of the immune system itself. In order to function properly, the immune system must be able to discern whether to mount an inflammatory attack against pathogens or whether to induce tolerance to self-antigen or commensals. Loss of the delicate balance between inflammatory versus regulatory responses underlies disease progression in many autoimmune disorders, chronic infections and cancer. Dendritic cells (DCs) are professional antigen presenting cells and have emerged as central players in initiating and regulating adaptive immune responses(Steinman et al., 2003; Steinman & Nussenzweig, 2002). Emerging evidence indicates that DCs also play a pivotal role in mediating tolerance against self-antigens, commensals and dietary antigens while mounting inflammatory responses against harmful pathogens(Manicassamy & Pulendran, 2011; Steinman & Nussenzweig, 2002). The types of cytokines secreted by the DCs dictate the outcome and type of immune response(Pulendran et al., 2010). For example, the cytokine IL-12 (p70) promotes IFN-γ–producing Th1 cells, whereas immune regulatory factors such as IL-10 and retinoic acid (RA) promote regulatory T cell (Treg) responses or Th2 responses(Pulendran et al., 2010). In contrast, cytokines such as TGF-β, IL-6, and IL-23 promote Th17 cell differentiation(Baeten & Kuchroo, 2013). Th1 and Th17 subsets of CD4+ effector T cells play a central role in the pathogenesis of several inflammatory diseases(Baeten & Kuchroo, 2013), while regulatory T cells (Tregs) play a critical role in suppressing inflammation and limiting autoimmunity(Sakaguchi et al., 2008). In contrast, T effector cells are critical for immune responses against infections and cancer. However, the receptors and signaling networks that program DCs into a tolerogenic or inflammatory state are poorly understood. Here, we review our current knowledge of the role of the Wnt pathway in regulating immune responses against self-antigen, cancer and microbes and highlight some unanswered questions.

The Wnt/β-catenin pathway in DCs

The Wnt pathway plays a critical role in cellular development, survival, proliferation, etc.(Clevers & Nusse, 2012; van Amerongen & Nusse, 2009), but the role of this pathway in immunity is beginning to become more well-defined(Staal et al., 2008). Wnts are secreted lipid-modified glycoproteins that bind to Frizzled (Fzd) receptors and activate multiple signaling pathways. In general, there are 19 Wnt proteins and 10 cognate Fzd receptors in humans(Clevers & Nusse, 2012; Staal et al., 2008). Wnts activate the canonical pathway that regulates transcription of target genes through the β-catenin/TCF pathway and the non-canonical pathway that is independent of β-catenin. For example, Wnt3a, Wnt5b and Wnt16 activate the β-catenin/TCF pathway in DCs, and Wnt5a activates the non-canonical pathway. Low-density lipoprotein receptor-related protein 5 (LRP5) and LRP6 co-receptors are critical signaling mediators of the canonical Wnt-signaling pathway (Clevers & Nusse, 2012). Our recent study has shown that DCs express both of the co-receptors LRP5 and LRP6(Suryawanshi et al., 2015). β-catenin, a transcriptional co-factor, is an important downstream mediator of LRP5 and LRP6 signaling (Clevers & Nusse, 2012). Wnt ligand interaction with FZD and co-receptor LRP5/6 results in the activation of β-catenin in the cytoplasm and its translocation to the nucleus, where it interacts with T-cell factor/lymphoid enhancer factor (TCF/LEF) family members and regulates the transcription of several target genes (Clevers & Nusse, 2012; Staal et al., 2008). In the absence of Wnt signaling, glycogen synthase kinase 3β (GSK-3β) phosphorylates β-catenin, resulting in its ubiquitination by β-transducin repeat containing (β-TrCP) protein, leading to proteosomal degradation (Clevers & Nusse, 2012; Staal et al., 2008).

Exposure to Wnts induces regulatory DCs

Several reports demonstrate that exposure to Wnts can condition DCs to a regulatory state(Oderup et al., 2013; Shen et al., 2014; Suryawanshi et al., 2015; Valencia et al., 2011). For example, DCs are conditioned in vitro in the presence Wnt3a and Wnt5a to exhibit regulatory functions (Oderup et al., 2013; Shen et al., 2014; Suryawanshi et al., 2015; Valencia et al., 2011). These tolerogenic DCs produce high levels of regulatory factors IL-10, TGF-β, retinoic acid (RA), IL-27 and VEGF, and they produce low levels of inflammatory cytokines such as IL-6, IL-12 and TNF-α in response to various TLR ligands(Manoharan et al., 2014; Oderup et al., 2013; Shen et al., 2014; Suryawanshi et al., 2015; Valencia et al., 2011). Furthermore, Wnt-conditioned DCs promoted regulatory T cell responses and can suppress disease in experimental models of multiple sclerosis(Manoharan et al., 2014; Suryawanshi et al., 2015). Wnt3a activates the β-catenin/TCF pathway in DCs while Wnt5a, which signals independently of the β-catenin pathway, also reprograms DCs to limit the expression of inflammatory cytokines (Oderup et al., 2013; Suryawanshi et al., 2015; Valencia et al., 2011). Ex-vivo conditioning of DCs with Wnts does not affect DC maturation and expression of co-stimulatory molecules in response to TLR ligands(Oderup et al., 2013; Suryawanshi et al., 2015).

Wnt-independent activation of the β-catenin pathway in DCs

β-catenin is a key downstream mediator of canonical Wnt signaling in DCs (Manicassamy et al., 2010; Oderup et al., 2013; Suryawanshi et al., 2015). In parallel, other studies have shown that multiple signaling pathways activate β-catenin independent of Wnts (Figure 1). For example, disruption of E-cadherin–E-cadherin interactions in DCs activates β-catenin signaling, which in turn programs DCs to a tolerogenic state (Jiang et al., 2007). Importantly, these tolerogenic DCs produce high levels of IL-10 and can protect mice against experimental autoimmune encephalomyelitis (Jiang et al., 2007). Our recent study has shown that TLR2-mediated signals via the PI3K/Akt pathway activates β-catenin in DCs and induces the expression of vitamin A metabolizing enzymes and IL-10(Manoharan et al., 2014). Interestingly, activation of the TLR2-pathway in DCs promotes T regulatory cell differentiation and suppressed chronic inflammation, and it protected mice from Th17/Th1-mediated autoimmune neuroinflammation(Manicassamy et al., 2009; Manoharan et al., 2014). Likewise, other signaling pathways, such as TLR3(Gantner et al., 2012), TLR9(Manoharan et al., 2014), FAS (Qian et al., 2013), TGF-β (Vander Lugt et al., 2011), and PLC-γ2 (Capietto et al., 2013) activate or regulate β-catenin in DCs and regulate adaptive immunity.

Figure 1. Mechanisms of tolerance induction via the β-catenin/TCF/LEF signaling axis.

Figure 1

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β-catenin may be activated and upregulated by a number of signaling components, and the canonical Wnt pathway serves as one of the most critical mechanisms for its expression. Upon interaction of Wnt ligands with cognate Fzd receptors and LRP5/6 coreceptors, β-catenin is activated and translocates to the nucleus to interact with TCF/LEF transcription factors, which leads to target gene transcription. Additional β-catenin activators include PI3K/AKT signaling through TLR 2,6 stimulation, CD95/ERK signaling, and activation via disruption of E-cadherin interactions. β-catenin/TCF/LEF-mediated target gene transcription results in expression of anti-inflammatory cytokines, such as IL-10 and IL-27, which induce Type 1 regulatory T (Tr1) cells, and TGF-β, which may induce FoxP3+ regulatory T (Treg) cells. In addition, vitamin A metabolizing enzymes (RALDH 1/2) are produced to convert vitamin A to retinoic acid (RA), which also induces Treg differentiation. Accumulation of Tregs in the tissue microenvironment may result in inhibition of pro-inflammatory Th1/Th17 cells. Pharmacological inhibition of Wnt/β-catenin may thus result in antitumor immunity, whereas use of pharmacological activators may lead to regression of inflammatory autoimmunity.

Control over breakdown of tolerance and autoimmunity by the Wnt pathway

Breakdown in immunological tolerance to self-antigens or uncontrolled inflammation results in autoimmune disorders(Steinman et al., 2003; Steinman & Nussenzweig, 2002). DCs play a critical role in regulating tolerogenic responses to self-antigens, as depletion of DCs in mice leads to severe autoimmune disease under steady-state conditions(Ohnmacht et al., 2009). Furthermore, DCs have been implicated in a variety of autoimmune diseases(Manicassamy & Pulendran, 2011). Several observations in mice and humans show that DCs can exert both pathogenic and protective roles in several autoimmune diseases, including inflammatory bowel disease and celiac diseases(Rescigno & Di Sabatino, 2009), rheumatoid arthritis(Wenink et al., 2009), type 1 diabetes (Pechhold & Koczwara, 2008), , and multiple sclerosis (Manicassamy & Pulendran, 2011). Multiple factors contribute to a breakdown in the tolerogenic potential of DCs, resulting in inflammatory diseases(Manicassamy & Pulendran, 2011).

Aberrant Wnt-signaling pathways are associated with several human inflammatory diseases (Clevers & Nusse, 2012; Joiner et al., 2013). Interestingly, Wnt ligands are highly expressed in several inflammatory diseases and metabolic diseases, such as arthritis (Rabelo Fde et al., 2010), atherosclerosis (Marinou et al., 2012), psoriasis (Gudjonsson et al., 2010), inflammatory bowel disease (Hughes et al., 2011), and neurodegenerative (Harvey & Marchetti, 2014) and neuroinflammatory diseases (Marchetti & Pluchino, 2013). However, the functional and biological significance of the Wnt signaling pathway in regulating ongoing inflammation and establishing immune homeostasis is poorly understood. In this context, recent studies have highlighted a critical role for the Wnt/β-catenin pathway in DCs in containing inflammation and limiting immune-mediated pathology.

Inflammatory Bowel disease (IBD)

Inflammatory bowel diseases (IBDs) such as ulcerative colitis and Crohn's disease are characterized by chronic intestinal inflammation induced by the dysfunctional relationship between the host immune system and the benign commensal flora(Rescigno & Di Sabatino, 2009). Intestinal dendritic cells (DCs) and macrophages play a pivotal role in mediating mucosal tolerance and suppressing intestinal inflammation(Rescigno & Di Sabatino, 2009). In IBD, these cells lose their tolerogenic properties, resulting in uncontrolled intestinal inflammation. Our previous work has shown that Wnts are highly expressed in the intestine and that β-catenin signaling is highly active in intestinal DCs and macrophages(Manicassamy et al., 2010). In mice, conditional deletion of β-catenin specifically in DCs and macrophages lead to strikingly reduced numbers of Foxp3+ and IL-10+ regulatory T cells with enhanced frequencies of Th1 and Th17 cells in the intestine but not in the spleen(Manicassamy et al., 2010). Further mechanistic study showed that intestinal DCs and macrophages deficient in β-catenin expressed reduced levels of immune regulatory genes involved in the synthesis of retinoic acid and IL-10 production. Moreover, these DCs expressed high levels of inflammatory cytokines in response to commensal microbiota under a steady state. Furthermore, mice that specifically lack β-catenin in DCs are more susceptible to DSS-induced colitis (Fevr et al., 2007; Manicassamy et al., 2010). In addition, Wnt/β-catenin signaling is critical for tissue repair and wound healing in the intestine(Fevr et al., 2007).

Multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory neurological disease resulting in multifocal demyelination in white matter of the human CNS that leads to debilitating motor and sensory dysfunction. Using experimental autoimmune encephalomyelitis (EAE), a mouse model for MS, studies have shown that DCs play a critical role in initiation and development of CNS pathology (Ganguly et al., 2013; Steinman et al., 2003; Terry et al., 2014). DCs contribute to disease pathology by inducing the differentiation of myelin-specific Th1 and Th17 cells (Bettelli et al., 2007; Hirota et al., 2011). In addition to CD4 effector T cells, CD8+ T cells also contribute to CNS pathology during EAE and MS (Huseby et al., 2001; Ji & Goverman, 2007). Conversely, emerging evidence suggests that DCs are also critical in resolving inflammation and limiting immune-mediated pathology in EAE by producing immune regulatory factors that induce T regulatory (Treg) cell activation (Manicassamy & Pulendran, 2011; Pulendran et al., 2010; Steinman et al., 2003). In this context, our recent study has shown that, during the induction and effector phase of EAE, the canonical Wnt-signaling pathway in DCs regulates the magnitude of inflammatory responses and limits collateral damage to the host(Suryawanshi et al., 2015). Accordingly, DC-specific deletion of coreceptors LRP5 and LRP6 or downstream mediators (β-catenin) of canonical Wnt-signaling exacerbated disease pathology. In contrast, DC-specific expression of active β-catenin or pharmacological activation of β-catenin signaling delayed EAE onset with diminished CNS pathology. Mechanistically, Wnt/β-catenin-mediated signaling in DCs limits Th1 and Th17 cell differentiation but promotes regulatory T cell responses by regulating the expression of anti- and pro-inflammatory cytokines(Suryawanshi et al., 2015). In addition to direct activation of β-catenin in DCs by Wnts, TLR2-mediated signals activate β-catenin in DCs and induce immune regulatory factors such as IL-10 and RA(Manicassamy et al., 2009; Manoharan et al., 2014). Activation of these receptors in DCs delayed EAE onset with reduced disease severity by inducing regulatory T cell responses(Manicassamy et al., 2009; Manoharan et al., 2014). Likewise, disruption of E-cadherin–E-cadherin interactions between DCs activates β-catenin and promotes ‘alternative’ maturation of immature DCs, with impaired immune stimulatory capacity(Jiang et al., 2007). Interestingly, immunization of these tolerogenic DCs into mice suppressed chronic inflammation and protected mice from Th17/Th1-mediated EAE(Jiang et al., 2007). In parallel, recent studies have shown that sustained activation of the Wnt-pathway restrains inflammation, incites neuroprotection and promotes neurogeneration (Marchetti & Pluchino, 2013). Collectively, these studies illustrate an important role for Wnt/β-catenin signaling in programming DCs to promote tolerance and suppress neuroinflammation .

Other autoimmune diseases

Aberrant Wnt/β-catenin signaling has been linked to development of several other immune-mediated autoimmune diseases such as lupus and arthritis. For example, in murine models of SLE, increases in serum DKK1 protein (a negative regulator of the Wnt/β-catenin pathway) were observed(Tveita & Rekvig, 2011). Likewise, increased expression of DKK1 in the serum of SLE patients was observed, suggesting altered canonical Wnt signaling in the development of Lupus(Wang et al., 2014). However, it is not known whether increases in the levels of negative regulators of the Wnt pathway alter functions of dendritic cells or macrophages. In contrast to the canonical Wnt-pathway, aberrant expression of Wnts such as Wnt5a and Wnt7B that activate the non-canonical pathway was observed in the joints of rheumatoid arthritis patients(Miao et al., 2013). Conversely, effects of these Wnts on immune cell function are not known. Thus, activating the Wnt/β-catenin pathway represents a potential therapeutic approach towards suppressing inflammation and limiting immune-mediated pathology.

Wnt/β-catenin signaling in tumor-induced immune tolerance

Tumors actively suppress antitumor immunity, and DCs play an important role in this (Munn & Mellor, 2007; Palucka & Banchereau, 2012; Rabinovich et al., 2007). Dysregulation of the Wnt pathway has been implicated in many tumors, and many tumors express high levels of Wnts(Reya & Clevers, 2005). Most studies have been directed towards how the Wnt signaling cascade regulates cancer development, progression and metastasis (Anastas & Moon, 2013; Fodde & Brabletz, 2007; Huang & Du, 2008; Larue & Delmas, 2006; Macheda & Stacker, 2008; Reya & Clevers, 2005). However, its effect on host antitumor immunity and tumor-induced immune tolerance remain unknown. In this context, recent studies have shown that Wnts in the tumor microenvironment can also initiate paracrine signaling within the immune cells and can regulate host antitumor immunity(Fu et al., 2015; Hong et al., 2015; Liang et al., 2014). In one of our own recent studies, using murine tumor models, we have shown that tumors program DCs to produce retinoic acid (RA), which promotes immune suppression by inducing regulatory T cell responses(Hong et al., 2015). Mechanistically, this is due to dendritic cells in the tumor microenvironment (TME) acquiring the ability to metabolize vitamin A to produce RA. In addition, DCs in the TME express high levels of IL-10, which contributes to immune suppression by inducing IL-10-producing CD4+ and CD8+ T cells(Hong et al., 2015). Induction of IL-10 in DCs is also dependent on the β-catenin/TCF pathway. In line with these observations, conditional deletion of β-catenin in DCs in mice markedly reduced T regulatory responses with delayed tumor growth(Honget al., 2015). Similarly, DC-specific deletion of Wnt co-receptors low-density lipoprotein receptor-related protein 5 and 6 (LRP5/6) in mice markedly delayed tumor growth and enhanced host anti-tumor immunity. Tumors can also modulate DC function by regulating its activation and maturation or by regulating the expression of co-stimulatory (CD80, CD86, CD40) and co-inhibitory molecules (PD-L1, PD-L2)(Rabinovich et al., 2007). Deletion of β-catenin in DCs resulted in increased surface expression of co-stimulatory molecules and decreased expression of co-inhibitory molecules(Hong et al., 2015). This phenotype is associated with DCs in an immunogenic state, resulting in enhanced anti-tumor immunity. In addition to inducing regulatory T cells, β-catenin activation in DCs can also affect cross priming of CD8+ T cell responses against tumors (Liang et al., 2014). Though β-catenin is known to suppress DC activation and cross priming (Manicassamy & Pulendran, 2009), it remains to be determined whether β-catenin directly regulates DC activation or does so indirectly via RA and IL-10(Hong et al., 2015). In addition to activating β-catenin, Wnts also activate other pathways such as mTOR by inhibiting GSK-3β(Fu et al., 2015). A recent study has shown this pathway is critical for induction of IL-10 in DCs in response to tumor. Collectively, these studies show that blocking the Wnt/β-catenin pathway represents a potential therapeutic approach towards breaking tumor-mediated immune suppression and augmenting anti-tumor immunity.

The Wnt/β-catenin pathway in regulating inflammatory responses to pathogens

Effective clearance of infectious pathogens by host immune defense mechanisms is critical for optimum health and survival. In this context, DCs tune host immune responses against pathogens so that the infections or inflammation are constrained without causing immune mediated bystander tissue damage. Recent studies have highlighted an important role for the Wnt/β-catenin pathway in DCs and macrophages in regulating inflammatory responses to bacterial and viral infections(Cohen et al., 2015; Liu et al., 2012; Silva-Garcia et al., 2014). Pathogens such as Salmonella (Duan et al., 2007; Liu et al., 2012), Mycobacterium (Bansal et al., 2011), Citrobacter rodentium(Brown et al., 2011), Pseudomonas aeruginosa(Chen et al., 2013) and Helicobacter pylori(Gnad et al., 2010) regulate β-catenin levels by inducing activation or degradation. For example, Salmonella, Mycobacterium, and Citrobacter induce activation of β-catenin via the TLR-PI3K/AKT pathway(Brown et al., 2011; Duan et al., 2007; Liu et al., 2012), whereas Helicobacter pylori that resides in the stomach activates β-catenin via the LRP6 pathway(Gnad et al., 2010). In contrast, Pseudomonas promotes β-catenin degradation by targeting the E-cadherin complex(Chen et al., 2013). All these studies suggest that activation of β-catenin results in the expression of anti-inflammatory factors and limits the expression of inflammatory factors. However, it is not known whether β-catenin suppresses expression of inflammatory factors directly or indirectly by inducing the expression of immune regulatory factors such as IL-10, RA and TGF-β. In addition, β-catenin has been shown to interact with transcription factor NF-κB, a key transcription factor critical for expression of inflammatory cytokines (Deng et al., 2002). This NF-κB/β-catenin interaction reduces NF-κB DNA binding and transactivation activity and suppresses target gene expression (Deng et al., 2002). In contrast to its anti-inflammatory role, a recent study has shown that the β-catenin/IRF8 pathway in DCs is critical for immunity against Taxoplasma gondii and vaccinia virus. Furthermore, recent studies have shown that β-catenin also interacts with other transcription factors, such as PPARγ (Alastalo et al., 2011; Liu et al., 2006), Foxo (Hoogeboom et al., 2008; Yan & Lackner, 2012), VDR (Hoogeboom et al., 2008; Shah et al., 2006), IRF3 (Yang et al., 2010) and IRF8(Cohen et al., 2015), which are known regulators of DC function and inflammatory responses. Therefore, additional studies will be required to determine the role of β-catenin in the regulation of these transcription factors and their target gene expression in response to inflammation and infection.

Therapeutic benefits of regulating the Wnt/β-catenin pathway in diseases

As discussed thus far, DCs play a critical role in regulating both immunity and tolerance. The Wnt/β-catenin pathway plays an important role in this, and aberrant Wnt-signaling occurs in many human inflammatory diseases(Clevers, 2006). Hence, activating this pathway represents a potential therapeutic approach to suppressing inflammation and immune-mediated pathology. Moreover, small molecule activators or inhibitors of the Wnt/β-catenin pathway already exist, and more are in active preclinical development(Anastas & Moon, 2013; Chen et al., 2009). In this context, our recent study has shown that pharmacological activation of canonical Wnt/β-catenin signaling delayed EAE onset with diminished CNS pathology(Suryawanshi et al., 2015) (Figure 1). In contrast, in tumors, this pathway suppresses host antitumor immunity and promotes tumor growth. So, in cancer, blocking the Wnt pathway represents a potential therapeutic approach towards reducing tumor-mediated immune suppression and augmenting anti-tumor immunity(Fu et al., 2015; Hong et al., 2015). Furthermore, disruption of this pathway altered DC function in the TME, resulting in enhanced host antitumor immune responses(Hong et al., 2015) (Figure 1).

Summary

As evidenced from the discussion above, several recent studies have provided important insights into how the Wnt/β-catenin pathway programs DCs to regulate the balance between tolerance and inflammatory responses. Though moderate inflammation is essential for normal immune responses, uncontrolled, chronic and excessive inflammation leads to allergic and autoimmune diseases. Wnt/β-catenin signaling represents a molecular switch in antigen presenting cells to dampen excessive inflammation, thereby conferring host protection from immune-mediated pathology. While it is clear that Wnt-signaling can program DCs to stimulate robust regulatory T cell responses and contain inflammatory responses, several important questions remain. For example, how does the Wnt/β-catenin pathway regulate adaptive immune responses under homeostatic conditions, inflammation and cancer?; What are the down-stream mediators of the Wnt/β-catenin pathway?; What role does non-canonical Wnt signaling play in regulating immunity versus tolerance?; How do the canonical and non-canonical Wnt pathways act in concert in regulating tolerance?. Finally, the question of whether persistent chronic infections such as HIV, HCV or TB exploit the Wnt/β-catenin pathway and, if so, whether blocking this pathway would enhance the innate and adaptive immune response is unknown. Addressing these questions will guide the rational design of therapeutic vaccines that can reprogram the innate immune system towards tolerance in autoimmune disease or enhancing immune responses against cancer and chronic infections.

Acknowledgements

We gratefully acknowledge the generous support of the National Institutes of Health (DK097271 and AI04875) in our work.

Footnotes

Disclosure

The authors report no conflicts of interest.

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