The C-type lectin receptors (CLRs) belong to a large family of proteins that contain a carbohydrate recognition domain (CRD) and calcium binding sites on their extracellular domains. Recent studies indicate that many CLRs, such as Dectin-1, Dectin-2 and Mincle, function as pattern recognition receptors (PRRs) recognizing carbohydrate ligands from infected microorganisms. Upon ligand binding, these CLRs induce multiple signal transduction cascades through their own immunoreceptor tyrosine-based activation motifs (ITAMs) or interacting with ITAM-containing adaptor proteins such as FcRγ. Emerging evidence indicate that CLR-induced signaling cascades lead to the activation of nuclear factor kappaB (NF-κB) family of transcriptional factors through a Syk- and CARD9-dependent pathway(s). The activation of NF-κB plays a critical role in the induction of innate immune and inflammatory responses following microbial infection and tissue damages. In this review, we will summarize the recent progress on the signal transduction pathways induced by CLRs, and how these CLRs activate NF-κB and contribute to innate immune and inflammatory responses.
The immune response to pathogens is characterized by a biphasic response: the initial innate immune response and the subsequent pathogen-specific adaptive immune response. The innate immune response is mediated mainly by macrophages, dendritic cells and neutrophils, and occurs rapidly after these cells encounter a pathogen, while the adaptive immune response is controlled by T and B cells, which occurs several days after pathogen invasion. Although the innate immune response is not pathogen-specific, it is crucial for the development of the adaptive immune response. Phagocytic cells such as dendritic cells and macrophages will engulf extracellular pathogens, or virally infected host cells, and display pathogen-associated proteins to T cells in the lymph nodes. In this way, the innate immune system ‘tells’ the cells of the adaptive immune system that an infection has occurred, and the appropriate pathogen-specific adaptive lymphocytes are activated.
The phagocytosis of extracellular pathogens or apoptotic cells is a highly ordered process (reviewed in Ref. 1). Phagocytosis can be triggered by receptor engagement, and macrophages and dendritic cells in particular display pattern recognition receptors (PRRs) on the cell surface. These PRRs recognize pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns—these molecular patterns are fairly conserved proteins, carbohydrates or nucleic acid structures that are common to pathogens, or are displayed only in the case of cellular damage. The presence of PAMPs and damage-associated molecular patterns indicates an infection or tissue damage, and upon binding to PRRs, signal transduction pathways are triggered, which result in the activation of various transcription factors such as nuclear factor kappaB (NF-κB). The activation of transcription factors results in the production of pro-inflammatory cytokines and chemokines, which in turn attract leukocytes such as neutrophils to the site of pathogen invasion or tissue damage.
PRRs are germline-encoded receptors, and recognize a variety of ligands, including proteins, nucleic acids, carbohydrates and lipids. There are four recognized classes of PRRs: Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), NOD-like receptors (NLRs) and C-type lectin receptors (CLRs) (reviewed in Ref. 2).
TLRs are perhaps the best-characterized class of PRR (reviewed in Refs. 3–5). There are currently 10 identified TLRs in humans and 12 in mice. TLRs are expressed on both the surface of the cell (TLRs 1, 2, 4, 5, 6) and in the cytoplasm (TLRs 3, 7, 8, 9). Cell surface TLRs recognize a variety of PAMPs, including lipopolysaccharide, phospholipids, zymosan, flagellin and peptidoglycan, while cytoplasmic TLRs recognize DNA or RNA ligands. TLR signal transduction utilizes a TIR domain (Toll/IL-1 receptor) in the cytoplasmic region of the receptor, and most TLRs utilize the adaptor protein MyD88.6, 7 There is a MyD88-independent signaling pathway downstream of TLR3 and 4 that utilizes the adaptor protein TRIF,8 but regardless of the proximal adaptor proteins used, TLR ligation culminates in the activation of the transcription factors NF-κB and AP-1 (reviewed in Ref. 4).
RLRs are cytoplasmic receptors that recognize dsRNA from RNA viruses. There are three receptors in the RLR family: RIG-I, MDA5 and LGP2 (reviewed in Ref. 9). RIG-I and MDA5, but not LGP2, contain a caspase-associated recruitment domain (CARD) that is thought to interact with other CARD-containing adaptor proteins. RLR proteins retain an inactive conformation until the C-terminal domain encounters dsRNA. This interaction triggers a conformational change that allows the RLR CARD domain to interact with other CARD-containing proteins such as IPS-1.10, 11, 12, 13 RLR signaling culminates in the activation of NF-κB and IRF-3, leading to the production of antiviral type I interferons.
NLRs are a large family of receptors: there are 23 identified members in humans and 34 members in mice.2 Structurally, NLR proteins share a nucleotide-binding domain and a leucine-rich repeat domain. The major members of this family are NOD1, NOD2, NLRP1, NLRP3 and NLRC4. NOD1 and NOD2 function as cytoplasmic receptors for PAMPs such as bacterial peptidoglycan. Ligation of NOD1 and NOD2 results in the activation of NF-κB, as well as IRF3 and IRF7. Other NLR family members, such as NLRP1, NLRP3 and NLRC4, form ‘inflammasomes’, which are protein complexes that activate caspases, a family of serine proteases involved in apoptosis and other inflammatory pathways (reviewed in 14). Activated caspases (particularly, caspase-1) play a role in the processing of pro-inflammatory cytokines from an inactive to an active form. In this way, the NLRs may initiate both the synthesis of pro-inflammatory cytokines such as IL-1β via activation of the transcription factor NF-κB, and the processing of those pro-inflammatory cytokines via inflammasome-mediated caspase activation (reviewed in 15).
CLRs are PRRs that recognize carbohydrate ligands. The C-type designation is from their requirement for binding of calcium. This is a large family of proteins containing a signal transmembrane domain, and is divided into 17 groups based on functional and structural characteristics. Members of this receptor family contain a carbohydrate recognition domain (CRD), which mediates binding of the receptor to its carbohydrate ligand. Recent studies indicate that some of CLRs function as PRRs for the recognition of microbial components and internalize various glycoproteins and microbes for the purposes of clearance and antigen presentation to T lymphocytes. These CLRs bind to carbohydrate ligands and induce multiple signaling cascades, which lead to the activation of several transcription factors including NF-κB and induce inflammatory responses. In this review, we will summarize the recent progress on the signal transduction pathways induced by CLRs and how CLRs activate NF-κB, as well as the contribution of CLR-induced NF-κB activation to innate immune and inflammatory responses.
Structural characteristics of CLRs
The CLR is a family of carbohydrate-binding proteins containing calcium-binding sites and CRD in their extracellular domains. There are two CRD groups: those that preferentially bind mannose contain an EPN motif, and those that preferentially bind galactose contain a QPD motif (reviewed in 16). In addition to being characterized by their CRDs, CLRs can be considered classical or non-classical. Classical CLRs share conserved residues in the CRD and calcium-binding sites, and share conserved carbohydrate-binding motifs. In contrast, non-classical CLRs do not share conserved residues in the CRD, and may bind non-carbohydrate ligands.
Several genes that encode CLRs are located near the natural killer gene complex on chromosome 12 in humans and chromosome 6 in mice. These CLRs have been shown or implicated to be PRRs.17, 18, 19, 20 They are clustered into two distinct groups: the Dectin-1 cluster (composed of MICL, CLEC-2, CLEC9A, CLEC12B, CLEC-1, Dectin-1 and LOX-1)20 and the Dectin-2 cluster (composed of BDCA-2, DCAR, DCIR, Dectin-2, Clecsf8 and Mincle).17, 18, 19, 20
CLRs from the Dectin-1 group all have an extracellular CRD, a stalk region, a transmembrane region and a signal transduction domain in the intracellular tail (reviewed in 20). The cytoplasmic tail of Dectin-1, CLEC-2, CLEC9A and LOX1 contains immunoreceptor tyrosine-based activation motif (ITAMs) (Figure 1), and ligation of these receptors results in the induction of signaling cascades, leading to the activation of transcription factors. In contrast, the cytoplasmic tail of MICL, CLEC12B, and DCIR contains an immunoreceptor tyrosine-based inhibitory motif (Figure 1), and ligation of these receptor results in an inhibition of transcription factor activation.
CLRs in the Dectin-2 group are similar in structure to those of the Dectin-1 group, with one notable exception: the Dectin-2 family of CLRs contains a short cytoplasmic domain. They are categorized as classical CLRs. The C-terminal region of the gene encodes the extracellular domain, while the N-terminal region encodes the intracellular domain. The short intracellular domain of BDCA-2, DCAR, Mincle, Clecsf8 and Dectin-2 lacks signal transduction abilities (Figure 1), so these receptors typically pair with the FcRγ chain to mediate signaling after receptor ligation.21, 22 A positively charged residue in the transmembrane domain of the receptor mediates the interaction with the FcRγ chain.22, 23, 24 The ITAMs of the FcRγ chain mediate signal transduction (Figure 1).
Although the specificity of CRD domain for each CLR is not fully determined, earlier studies indicate that Dectin-1 recognizes β-glucan,25, 26 while Dectin-2 recognizes high Mannose such as Man9GlcNAc2 and Man8GlcNAc2,27 which are exposed on the surface of hyphal form of Candida albicans.28, 29 Although it is not fully characterized, it has been found that Mincle can bind to mycobacterial glycolipid, trehalose dimycolate (TDM),30, 31 α-mannose on the surface of pathogenic fungus, Malassezia32 and SAP130, a component of small nuclear ribonucloprotein from damaged cells.22 Recent studies indicate that stimulation of Dectin-1, Dectin-2 or Mincle with their ligands can effectively induce Syk- and CARD9-dependent signaling cascades, leading to activation of NF-κB and expression of inflammatory cytokines.22, 29, 31, 33
Regulation of NF-κB activation by different pathways
NF-κB is a family of 5 transcription factors: RelA (also known as p65), RelB, c-Rel, p50/p105 and p52/p100. These proteins form homo- or hetero-dimers via interactions between Rel homology domains, and play major roles in the immune response, as NF-κB controls the expression of genes involved in cell proliferation, apoptosis and lymphocyte activation, as well as controls the expression of many pro-inflammatory cytokines and chemokines (reviewed in 34, 35). Because of its pluripotent affects on the immune system, NF-κB activation is a tightly regulated process. There are two main pathways of NF-κB activation: the canonical and non-canonical pathways. The canonical pathway is activated following the stimulation of various types of receptors including TLRs and other PRRs, while the non-canonical pathway is activated following the stimulation of TNF receptor superfamily members such as CD40 or lymphotoxin β receptor. In the canonical pathway, the NF-κB dimer is retained in the cytoplasm through its association with an IκB protein, which masks the nuclear localization signal of the NF-κB dimer. Following receptor ligation, a positive signal transduction cascade is initiated and converged on the IκB kinase (IKK) complex. The IKK complex consists of IKKα and IKKβ, two catalytic subunits, and IKKγ/NEMO, a regulatory subunit. Activation of the IKK complex occurs following K63-linked ubiquitination of NEMO36, 37, 38 and phosphorylation of IKKα and IKKβ39 (reviewed in 40). The activated IKK phosphorylates IκB proteins on conserved serine residues. The phosphorylation of IκB proteins triggers their K48-linked ubiquitination and proteasome-mediated degradation,41, 42 freeing the NF-κB dimer to translocate to the nucleus. Once in the nucleus, the p65 subunit of the NF-κB dimer is phosphorylated and acetylated, which increases the dimer affinity for DNA and enhances transcriptional activity (reviewed in 43, 44). In the non-canonical pathway, receptor ligation triggers the activation of NF-κB-inducing kinase. Activated NF-κB-inducing kinase in turn activates IKKα, which phosphorylates p100, triggering the processing of p100 into p52. The RelB/p52 dimer is then free to enter the nucleus and mediate transcription of target genes (reviewed in 45). Although tremendous progresses have been made regarding to NF-κB signaling pathways induced by receptors such as TLRs, TNFR and antigen receptors (reviewed in 34, 35), the NF-κB signaling pathways induced by CLRs remains largely to be characterized.
Dectin-1, Dectin-2 and Mincle signaling to NF-κB
Although how CLRs induce NF-κB activation remains to be determined, recent studies on Dectin-1, Dectin-2 and Mincle have revealed several signaling components mediating CLR-induced NF-κB activation. The ligation of Dectin-1, Dectin-2 or Mincle triggers receptor clustering and initiates signaling through its own ITAM or the ITAM in FcRγ (reviewed in 46, 47), leading to the canonical activation of NF-κB. Tyrosine residues in the ITAMs are phosphorylated by Src family kinases, although it remains to be determined which Src family kinases are involved in these signaling pathways. The phosphorylated ITAMs in Dectin-1 or in FcRγ following the stimulation of these receptors lead to the recruitment48 and activation of the kinase Syk (Figure 2).22, 31, 49, 50, 51 Syk activation is linked to the activation of a protein complex consisting of CARD9, BCL10 and MALT1 (Figure 2).33, 52 This CARD9–BCL10–MALT1 (CBM) complex is required for ITAM signaling to NF-κB and MAP kinases in myeloid cells,33, 53 which is similar to the CARMA1–BCL10–MALT1 complex that is required for antigen receptor signaling in lymphocytes (reviewed in 54). The current model posits that the CARD9–BCL10–MALT1 complex in myeloid cells behaves like the CARMA1–BCL10–MALT1 complex in lymphocytes, and transduces signals that culminate in the activation of the IKK complex.55, 56
Although many studies indicate that Syk functions upstream of the CBM complex, the mechanism by which Syk links to this CBM complex remains to be determined.48 Our recent studies indicate that CARD9 deficiency does not affect Dectin-2-induced phosphorylation of IKK complex but only impairs the polyubiquitination of NEMO in the IKK complex, suggesting that this CBM complex is required for NEMO polyubiquitination (Figure 2).57 In contrast, PLCγ2, a downstream component of Syk, is required for Dectin-2-induced phosphorylation of IKK complex and NF-κB activation (Figure 2).58 Since PLCγ2 is required for NF-κB activation induced by both Dectin-1 and Dectin-2 pathways,58 it is likely that PLCγ2 is also a key component downstream of Syk in the signaling pathways induced by other CLRs. However, it remains to be determined whether PLCγ2-dependent signaling regulates the CBM complex (Figure 2).
Dectin-1 ligation also triggers the non-canonical activation of NF-κB. Curdlan or C. albicans stimulated dendritic cells showed nuclear translocation of both p65 and the non-canonical subunit RelB in a Syk-dependent manner. Interestingly, Dectin-1 ligation also activates Raf-1 in a Syk-independent manner, and Raf-1 acts to promote p65 activity and repress RelB activity.59 Therefore, although Dectin-1 activates non-canonical NF-κB activation, the functional consequences of this activation are minimized by the activity of Raf-1. It is unclear if stimulation of Dectin-1 with other ligands will trigger the activation of both Syk and Raf-1, or if the activation of these two pathways can occur separately. Furthermore, additional research is needed to determine how Syk triggers non-canonical NF-κB activation.
Cross-talk between CLRs and other PRRs
PAMPs and damage-associated molecular patterns do not occur in a vacuum, and it is common for several different PRRs to be engaged at the same time following pathogen encounter or tissue damage. When this occurs, signals from the PRRs are integrated to shape the developing immune response to ensure effective pathogen control or tissue repair.
PRR cross-talks can result in the enhancement or abrogation of an immune response. For example, zymosan is a preparation of Saccharomyces cerevisiae cell wall components that has been shown to signal through Dectin-1 and TLR1, TLR2 and TLR6.25, 60 It has been shown that Dectin-1 mediates phagocytosis and reactive oxygen species production following zymosan binding, and enhances TLR2 activation of NF-κB and production of IL-12 and TNF-α in response to live yeast.61, 62 Dectin-1 ligation alone did not trigger cytokine production, and TLR2 binding did not result in phagocytosis or reactive oxygen species production; it was only after both receptors were engaged that macrophages were fully activated, indicating a need for simultaneous TLR and CLR input in the immune response.
Dectin-1, Dectin-2 and NOD2 have been shown to synergize in a model of zymosan-induced arthritis. Zymosan-induced arthritis is a model of septic arthritis, which may occur as a consequence of a systemic infection (reviewed in 63). Both Dectin-1 and Dectin-2 (to a lesser extent) contributed to the development of zymosan-induced arthritis, and interestingly, NOD2 deficient mice showed reduced development of zymosan-induced arthritis, suggesting all three receptors are important in this process.64
Dectin-1 has also been shown to synergize with galectin-3, another C-type lectin receptor.65 These two proteins were shown to physically associate with each other, as evidenced by co-immunoprecipitation, and knockdown of galectin-3 resulted in a four-fold decrease of TNF-α production by macrophages stimulated with C. albicans. Dectin-1 binds to β-glucans, while galectin-3 binds to β-1,2-oligomannans, which are present in the cell wall of pathogenic fungi, but are absent from the cell walls of non-pathogenic fungi such as S. cerevisiae. This suggests that galectin-3 helps distinguish pathogenic from non-pathogenic fungi, and the data from this paper support that conclusion, as knockdown of galectin-3 did not affect macrophage production of TNF-α after stimulation with S. cerevisiae. Galectin-3 has also been shown to associate with TLR-2, and the data indicate that it plays a similar role in pathogen discrimination.66
The physical association of galectin-3 with both Dectin-1 and TLR-2 suggests the interesting possibility that additional PRRs form heterodimers, which would potentially enhance the cells ability to recognize pathogens and transduce activating signals. It is tempting to speculate that such heterodimers would function as receptors with dual specificity, thereby providing another means of fine tuning of the immune response. Furthermore, an inhibitory receptor such as DCIR may pair with an activating receptor such as Dectin-1 to control the immune response. One can imagine a scenario in which DCIR inhibits macrophage activation in the presence of non-pathogenic fungi, or in the presence of the yeast form of a pathogen, but in the presence of the fungal form of the pathogen, the ligand for DCIR is no longer present and Dectin-1 signaling results in macrophage activation. Additional research is needed to determine if other PRRs form physical complexes, and how those complexes affect signal transduction and cellular activation. Furthermore, it will be interesting to see if macrophages and dendritic cells utilize different PRR combinations to signal upon pathogen encounter.
Some CLRs modulate TLR signaling to dampen immune responses. A good example of this phenomenon is DC-SIGN, a receptor that binds to endogenous ligands such as ICAM-3,67 several viruses,68, 69, 70, 71, 72 Mycobacterium tuberculosis73 and the fungal pathogen Candida albicans.74 In the case of M. tuberculosis, DC-SIGN binds to the bacterial ligand ManLAM (mannose-capped lipoarabinomannans), and this interaction inhibits TLR-2- and TLR-4-mediated dendritic cell maturation, stimulates the production of the immunomodulatory cytokine IL-1075 and inhibits TLR4-mediated IL-12 production.76 In this way, DC-SIGN signaling modulates the immune response to M. tuberculosis and contributes to bacterial survival.
Functional consequences of Dectin-1, Dectin-2 and Mincle signaling
Dectin-1, Dectin-2 and Mincle ligation has been shown to affect how the adaptive immune response develops. For example, Dectin-2 signaling was shown to be critical for the development of a TH17 response in a murine model of systemic candidiasis.51 Dectin-2−/− dendritic cells showed reduced cytokine production after encounter with C. albicans-mannans, and Dectin-2−/− mice showed increased susceptibility to C. albicans infection, demonstrating the importance of Dectin-2 in the immune response to Candida species.29 Mechanistic studies have demonstrated that Dectin-2 ligation triggers the expression of IL-1β and IL-23p19, due to the MALT1-mediated activation of c-Rel only. This is in contrast to Dectin-1 signaling, which results in the activation of p65, RelB and c-Rel.77 These results indicate that while Dectin-1 ligation triggers the production of multiple pro-inflammatory cytokines (including those important for the development of a TH17 response), Dectin-2 ligation specifically induces pro-TH17 cytokines only, and highlights the importance of Dectin-2 signaling in the development of TH17 responses.
Dectin-1 signaling has been implicated in the immune system's discrimination of yeast and hyphal forms of C. albicans. Since C. albicans commonly colonizes the skin and mucosal surfaces, it is important for the immune system to distinguish between Candida as a commensal organism (yeast form) and an invasive pathogen (hyphal form). To that end, Candida hyphae were shown to stimulate IL-1β production in macrophages, while Candida yeast did not trigger this cytokine production. Both Dectin-1 and the inflammasome were shown to contribute to hyphal-mediated IL-1β production, indicating that Dectin-1 plays a role in the differential recognition of Candida.78
Mincle signaling has been shown to play a role in the clearance of dead cells, indicating a potential role for this receptor in wound healing and non-infectious inflammation. In addition to recognizing fungal ligands, Mincle was shown to bind SAP130, a nuclear protein that is released upon cell death (a ‘danger’ signal). When Mincle signaling was blocked in vivo, there was a reduced accumulation of macrophages and neutrophils to the thymus following whole body irradiation of mice, indicating a role for Mincle in the recruitment of inflammatory cells to non-infectious sites of cell death.22
The importance of Dectin-1, Dectin-2 and Mincle signaling is especially apparent when these receptors are absent or signaling does not occur properly. In patients undergoing hematopoietic stem cell transplantation, the presence of the early-stop codon mutation Y238 in the gene encoding Dectin-1 in either donors or recipients was associated with increased risk of invasive aspergillosis infection, indicating a role for Dectin-1 in the immune response to this pathogen.79 In mice, the absence of Dectin-1 results in increased susceptibility to C. albicans and pulmonary Aspergillus fumigatus infection.80, 81 Finally, Dectin-1-deficient mice were shown to be more susceptible to Pneumocystis carinii infection, but not C. albicans infection, indicating that Dectin-1 is not absolutely required for the immune response to all fungal pathogens.82
The human Y238 Dectin-1 mutation is also associated with an increased incidence of chronic mucocutaneous Candida infection. Peripheral blood mononuclear cells from patients homozygous for this mutation showed reduced IL-6, TNFα and IL-17 production following stimulation with β-glucan or C. albicans yeast or hyphae, but phagocytosis of yeast was normal, indicating that while Dectin-1 plays an important role in activating monocytes, it is dispensable for the phagocytosis of Candida.83
Dectin-2 deficiency is associated with a reduction in TH17 responses, as discussed above. Finally, a recent report details the requirement for Mincle signaling in the immune response to Fonsecaea pedrosoi, a fungus that causes the chronic skin infection chromoblastosis. It was demonstrated that both Mincle and TLR signaling are required to trigger an immune response against this fungus, again highlighting the non-redundant functions of different classes of PRR.84
Interestingly, Mincle is an important receptor for macrophage recognition of M. tuberculosis. Mincle recognizes the mycobacterial cord factor TDM, and Mincle is required for macrophage production of IL-6 following TDM stimulation.30, 31 Furthermore, Mincle-deficient mice showed reduced TH17 responses to immunization with a synthetic TDM analog, and Mincle-deficient macrophages showed impaired production of IL-6 following exposure to M. bovis bacillum Calmette-Guérin. Taken together, these data indicate a role for Mincle in the immune response to Mycobacterial species.30, 31
Given the importance of CARD9 in CLR signaling, it is not surprising that CARD9 deficiency is linked to impaired fungal immune responses. An early stop codon mutation in the gene encoding CARD9 (Q295X) is associated with an increased incidence of both mucocutaneous and invasive Candida infections in human patients. Patients homozygous for this mutation have a lower number of TH17 cells than normal controls, again highlighting the importance of this signaling pathway in the development of the TH17 response. Studies in mice showed that this mutation results in a loss of function of CARD9, and peripheral blood mononuclear cells from patients homozygous for this mutation showed no CARD9 expression, although the expression of an N-terminal fragment could not be ruled out.85
While Dectin-1 mutations are associated with a susceptibility to mucocutaneous Candida infections, the mutation of CARD9 results in a more severe phenotype, with a susceptibility to both mucocutaneous and invasive Candida infections. This is not surprising, as a defect in CARD9 will have more global effects, impairing signaling from Dectin-1, Dectin-2, Mincle and other PRRs, while Dectin-1 mutations only affect Dectin-1 signaling. Although Dectin-1 is not a redundant receptor, other PRRs such as Dectin-2, Mincle and some TLRs can contribute to the initiation of an antifungal immune response.
Targeting CLRs for immunotherapy
Given their importance in the immune system, it is not surprising that a growing number of vaccine or drug treatment strategies aim to target CLRs to either enhance or suppress the immune response (reviewed in 86).
DEC205 is a CLR expressed by dendritic cells, and several papers have shown that including antibodies to DEC205 is an efficient way to target DNA or protein vaccines to dendritic cells, where the antigen can then be displayed to T cells.87, 88, 89, 90 Another CLR, Clec9A, has also been shown to be an effective means of targeting vaccine components to dendritic cells,91 indicating that other CLRs may be useful for targeting dendritic cells.
DEC205 has also been targeted to induce tolerance, as anti-DEC205 was used to deliver the pancreatic β-islet cell mimotope MimA2. This strategy resulted in the deletion of autoreactive CD8+ T cells, and the induction of tolerance in the diabetogenic NOD mouse model,92 suggesting the possibility of targeting CLRs to induce tolerance in other autoimmune disorders such as arthritis.
Interestingly, the administration of zymosan to early hyperglycemic mice prevented their conversion to diabetes, suggesting that TLR-2 and Dectin-1 signaling can induce immune tolerance. Further experiments showed that zymozan treatment resulted in a decrease in immune cell infiltrate in β-islets, reduced β-islet destruction, increased naive or regulatory T cell phenotype and enhanced regulatory T suppressor function.93 TLR-2 and Dectin-1 ligation by zymosan was shown to induce IL-10 and TGF-β expression, but it is unclear if these results are solely due to suppressive cytokine expression. Taken together, these data suggest that CLR targeting may induce immune tolerance through the induction of regulatory T cells, or by enhancing the activity of existing regulatory T cells.
CLR targeting has also been used to improve anti-tumor responses. Targeting ovalbumin antigen to the human mannose receptor was shown to reduce tumor burden in human mannose receptor-expressing mice, when the mice were inoculated with ovalbumin expressing melanoma cells.94 This strategy has also been shown to be effective using the endogenous melanoma antigen pmel17.95 In summary, various CLRs may be targeted to enhance the immune response to infectious agents or tumors, and further research is needed to identify the most promising vaccine strategies.
CLRs are a vital part of the innate immune response, playing a role in the immediate recognition of pathogens and shaping how the adaptive immune response develops. CLRs may synergize with other PRRs to coordinate the developing immune response, ensuring the appropriate discrimination of pathogens and activating the leukocytes needed to fight infection. CLRs may also contribute to the development of autoimmune disorders, and some CLRs may play a role in wound healing and the clearance of dead cells. Targeting CLRs has shown to be an effective means of improving vaccine efficacy, but may also work to induce tolerance in some situations. In summary, CLRs are a diverse family of receptors that play many roles in the immune system, but many questions remain. For instance, there are many receptors with unidentified ligands. Identifying the ligands that trigger receptor signaling will provide new targets for therapies, and will contribute to our understanding of how these receptors influence the immune response. Do these receptors form dimers? Evidence from galectin-3 suggests that some CLRs form dimers with other PRRs—is this true for other CLRs as well? What precise molecular events are triggered following CLR ligation? It is known that Syk and CARD9 are important in this process, but are their other proteins involved in this pathway? Identifying other molecular players in CLR signaling will provide additional targets for immunomodulatory therapies. Finally, how can CLRs be targeted to improve vaccine efficacy, or to induce tolerance in autoimmune disorders. Promising work with DEC205 has been performed, but can other CLRs be targeted to the same or greater effect? It will be exciting to see how these and other questions are answered in the years to come.
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This work was supported by grants from the National Institutes of Health (AI050848, GM065899 and GM079451) to XL. LM Kingeter is supported by the Odyssey Postdoctoral Fellowship from MD Anderson Cancer Center.
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Kingeter, L., Lin, X. C-type lectin receptor-induced NF-κB activation in innate immune and inflammatory responses. Cell Mol Immunol 9, 105–112 (2012). https://doi.org/10.1038/cmi.2011.58
- C-type lectin receptor
- innate immunity
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