The recognition of β-glucans by dectin-1 has been shown to mediate cell activation, cytokine production and a variety of antifungal responses. Here, we report that the functional activity of dectin-1 in mucosal immunity to Candida albicans is influenced by the genetic background of the host. Dectin-1 was required for the proper control of gastrointestinal and vaginal candidiasis in C57BL/6, but not BALB/c mice; in fact, the latter showed increased resistance in the absence of dectin-1. The susceptibility of dectin-1-deficient C57BL/6 mice to infection was associated with defects in IL-17A and aryl hydrocarbon receptor-dependent IL-22 production and in adaptive Th1 responses. In contrast, the resistance of dectin-1-deficient BALB/c mice was associated with increased IL-17A and IL-22 production and the skewing towards Th1/Treg immune responses that provide immunological memory. Disparate canonical/noncanonical NF-κB signaling pathways downstream of dectin-1 were activated in the two different mouse strains. Thus, the net activity of dectin-1 in antifungal mucosal immunity is dependent on the host's genetic background, which affects both the innate cytokine production and the adaptive Th1/Th17 cell activation upon dectin-1 signaling.
Pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and C-type lectin receptors, particularly dectin-1, are essential determinants of host antifungal immunity.1, 2, 3 Dectin-1 is a major β-glucan receptor expressed on the surface of a variety of cells, including myeloid4 and epithelial cells.5, 6 This receptor recognizes β-1,3-glucans that are exposed on particles such as zymosan and many fungi, including species of Candida, Aspergillus and Pneumocystis,7, 8, 9 either alone or in conjunction with other PRRs, most notably TLR2 and the mannose receptor.10 As the principal non-opsonic receptor involved in fungal uptake,11 dectin-1 engagement mediates cell activation, cytokine production and a variety of antifungal responses through the spleen tyrosine kinase (Syk)/caspase recruitment domain-containing protein 9-dependent pathway.12 Recently, dectin-1 was also shown to signal through Raf-1 and both Syk- and Raf-1-dependent pathways, converging at the level of NF-κB activation to control adaptive immunity to fungi.13
Although the crucial role of dectin-1 in antifungal immunity is undisputed both in mice and humans, the precise mechanisms by which dectin-1 signaling contributes to innate and adaptive immune resistance to mucosal and systemic candidiasis have not been completely clarified. The recent discovery of a genetic polymorphism in the human DECTIN1 gene, Y238X, which generates a truncated protein with impaired cell surface expression and decreased ligand-binding ability, points to the important antifungal function of dectin-1 in humans.14 Indeed, Y238X carriers were more susceptible to mucocutaneous candidiasis14 and displayed increased frequency of oral and gastrointestinal colonization with Candida species when undergoing allogeneic stem cell transplantation.15 Interestingly, the Y238X polymorphism had no associated risk with systemic candidiasis, likely due to unimpaired phagocytosis and the killing of C. albicans by host leukocytes.15 Thus, in both humans and mice,16 dectin-1 appears to be crucially involved in the control of mucosal candidiasis, while discrepant results have been observed for its role in systemic infection.
One of the most important mechanisms of dectin-1-mediated immune resistance relies on the activation of Th1 and Th17 cells. Th17 responses are thought to be important in the defense against C. albicans, as patients with diseases characterized by defective Th17 responses (e.g., chronic mucocutaneous candidiasis, hyper IgE syndrome and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) show increased susceptibility to mucosal candidiasis.14, 17 While murine studies have failed to show an unequivocal role for dectin-1 in IL-17 production during systemic candidiasis,7, 8, 12, 18 the role of dectin-1 in the Th1/Th17 cell skewing in experimental mucosal candidiasis has never been directly addressed. Ultimately, the contrasting results in the different models may be related to the site-specific requirements of Th17 cells that are central to the control of mucosal, rather than systemic, infection.19
In the present study, we have directly assessed the contribution of the dectin-1/Th17 axis in different models of mucosal candidiasis using a side-by-side comparison of dectin-1 functional deficiency in genetically unrelated strains of mice. The contribution of dectin-1-mediated mechanisms of antifungal resistance was indeed found to depend to some extent on the genetic background of the host.5, 20 Macrophages from BALB/c and genetically related strains have been reported to express the full-length dectin-1A and the stalkless dectin-1B isoforms at comparable levels, whereas macrophages from the C57BL/6 background and related mice predominantly expressed the smaller isoform.21 The results of the present study demonstrate that the functional activity of dectin-1 in both gastrointestinal and vaginal candidiasis is contingent upon the host's genetic background and affects both innate cytokine production, as well as the adaptive Th1/Th17 cell activation.
Materials and methods
Female C57BL/6 and BALB/c mice, 8–10 weeks old, were purchased from Charles River Laboratories (Calco, Italy). Homozygous Dectin-1–/– mice in both C57BL/6 and BALB/c backgrounds were kindly provided by Emiko Kazama, University of Tokyo, Japan. All mice were housed in specialized pathogen-free facilities at the Animal Facility of Perugia University, Perugia, Italy, and were used in accordance with protocols approved by Animal Welfare Assurance A-3143-01.
The wild-type C. albicans strain MKY378,22 and the isogenic strains obtained by mutagenesis of the parental strain 3153A and that were either capable (referred to as virulent Vir3) or not (low-virulence Vir−3) of yeast-to-hyphae transition, as assessed by germ-tube formation in vitro,23 were used. Yeast cells were obtained by harvesting at the end of the exponential growth phase.
Unless otherwise stated, gastrointestinal infection was performed by inoculating mice intragastrically (i.g.) with 1×108 Vir3 or Vir−3 cells in 200 µl of saline using an 18-gauge 4-cm-long plastic catheter. Re-infection was performed 14 days after the primary i.g. infection by intravenous (i.v.) inoculation of 5×105 Vir3 cells. Quantification of fungal burden in the stomach, colon and kidneys of infected mice was performed at different days post-infection (dpi) by plating triplicate serial dilutions of homogenized organs in Sabouraud dextrose agar. The results are expressed as colony-forming units (CFUs) per organ (mean±SE). For histology, paraffin-embedded tissue sections (3–4 µm) of the stomach were stained with periodic acid-Schiff (PAS) reagent. Histology sections were observed using a BX51 microscope (Olympus, Milan, Italy), and images were captured using a high-resolution DP71 camera (Olympus).
Vaginal infection was performed by inoculating mice intravaginally with 5×106 Vir3 cells in 10 µl saline. Seventy-two hours prior to infection, the mice were injected subcutaneously with 0.1 mg estradiol benzoate (Sigma-Aldrich, St Louis, MO, USA) dissolved in 0.1 ml sesame oil. Estrogen treatments were continued at weekly intervals thereafter. Estrogen-treated control mice were treated with estrogen as described above and given saline intravaginally. Re-infection was performed by intravaginal inoculation with 5×106 Vir3 cells in intravaginally infected mice 3 weeks after the primary infection. To quantify vaginal fungal burden at different dpi, 100 µl vaginal lavage was directly plated onto Sabouraud dextrose agar plates supplemented with gentamicin (Sigma-Aldrich). After incubation at 37 °C for 48 h, the number of CFUs was calculated, and the results are expressed as the mean±SE.
Cytospin preparations of the lavage fluids were stained with May–Grünwald–Giemsa and analyzed for polymorphonuclear cell recruitment using a BX51 microscope equipped with a high-resolution DP71 camera (Olympus).
In vitro cultures
Peyer's patches (PPs) cells from naive mice were stimulated for 18 h in vitro with 10 µg/ml β-glucan (Sigma-Aldrich) prior to assessing Tnfa, p35, p19 and Il10 gene expression by real-time PCR. The expression of Il22 was assessed following stimulation with β-glucan as above or with 20 nM 6-formylindolo[3,2-b]carbazole (FICZ) (Enzo Life Sciences, Vonci-Biochem, Italy).
Canonical and noncanonical NF-κB signaling in dendritic cells (DCs)
Murine DCs were obtained by culturing bone marrow cells in RPMI medium containing 10% filtered bovine serum, penicillin, streptomycin, 2 mM l-glutamine in the presence of 20 ng/ml mouse recombinant granulocyte–macrophage colony-stimulating factor (PROSPECbio; Prodotti Gianni S.p.A. Milan, Italy) and 10 ng/ml rIL-4 (PROSPECbio) for 7 days to obtain CD11b+ DCs. Cells were stimulated with C. albicans Vir3 (1:1 ratio) for 30 min at 37 °C. We used the ELISA-based TransAM Flexi NF-κB Family Kit (Active Motif) to monitor the activity of NF-κB family members on nuclear extracts (Nuclear Extract Kit, TransAM Flexi NF-κB Family Kit).
Real-time reverse transcription PCR (RT-PCR)
Real-time RT-PCR was performed using the iCycler iQ detection system (Bio-Rad, Milan, Italy) and SYBR Green chemistry (Agilent Technologies, Milan, Italy). Total RNA was extracted from CD4+ T cells purified from the mesenteric lymph nodes (MLNs) of infected animals using an RNeasy Mini Kit (Qiagen, Milan, Italy) and was reverse transcribed with Sensiscript Reverse Transcriptase (Qiagen) according to the manufacturer's instructions. PCR primers were as described previously.23 The sense/antisense primers for Ahr were as follows: sense, 5′-TCCATCCTGGAAATTCGAACC-3′, and antisense, 5′-TCTTCATGCGTCAGTGGTCTC-3′. The thermal profile for real-time PCR was 95 °C for 3 min, followed by 45 cycles of denaturation for 1 min at 95 °C, annealing for 1 min at the appropriate temperature and extension for 30 s at 72 °C. Amplification efficiencies were validated and normalized against Gapdh expression. Each data point was examined for integrity by analysis of the amplification plot. The mRNA-normalized data are expressed as the fold increase over day zero.
Cytokine content was determined by enzyme-linked immunosorbent assays (R&D Systems, Milan, Italy) on stomach homogenates or vaginal lavage fluids. The detection limits (pg/ml) of the assays were <10 for IFN-γ, IL-17A, IL-17F and IL-17E and <3.2 for IL-22.
Statistical significance was assessed by ANOVA or unpaired Student's t-test with Bonferroni's correction using GraphPad Prism software (GraphPad Software, San Diego, CA, USA). P values ≤0.05 were considered statistically significant. Data are representative of at least two independent experiments or pooled from three to five experiments. The in vivo groups consisted of 6–8 mice/group.
The susceptibility of Dectin-1−/− mice to gastrointestinal candidiasis depends on the host's genetic background
Given that distinct expression patterns of dectin-1 isoforms have been described among genetically unrelated strains of mice,21 we assessed whether and how the host's genetic background influenced dectin-1 activity in mucosal candidiasis. For this purpose, we infected dectin-1-deficient mice i.g. in both the C57BL/6 and the BALB/c backgrounds with two different strains of C. albicans and assessed the pattern of susceptibility and/or resistance to infection in terms of fungal burden, inflammatory pathology, and innate and adaptive immunity. We found a contradictory role for dectin-1 in antifungal resistance that depended on the host's genetic background. Indeed, the susceptibility to gastrointestinal infection was increased in C57BL/6 Dectin-1–/– mice with both strains of C. albicans, as judged by the higher fungal burden in the stomach and colon at 4 and 7 dpi, as well as the dissemination to the kidneys (Figure 1a). A similar susceptibility phenotype was observed using a lower inoculum (5×106) of the Vir3 cells or with the low-virulence Vir−3 strain (Figure 1b). Both wild-type and Dectin-1–/– mice eventually cleared the infection (Figure. 1a). However, histological analysis of wild-type mice revealed a predominantly superficial infection with limited submucosal inflammation and inflammatory cell recruitment in the stomach, while Dectin-1–/– mice showed signs of massive inflammatory infiltrates, with extensive tissue invasion and parakeratosis, as well as hyphae that penetrated the mucosal barrier (Figure 1c). In contrast to what was observed in C57BL/6 mice, BALB/c Dectin-1–/– mice were more resistant to infection by either strain of C. albicans than wild-type mice, as judged by the decreased fungal burden, lack of peripheral dissemination (Figure 2a) and limited signs of inflammatory cell recruitment and mucosal hyperplasia (Figure 2c). Expectedly, BALB/c Dectin-1–/– mice were also more resistant to infection with the lower inoculum of the Vir3 or with the low-virulence Vir−3 strain (Figure 2b). These results clearly show that the susceptibility of Dectin-1–/– mice to gastrointestinal candidiasis depends largely on the host's genetic background and less on the fungal strains (at least with the fungal strains we have used).
To assess whether the susceptibility phenotypes of Dectin-1–/– mice on both the C57BL/6 and BALB/c backgrounds were retained in vaginal candidiasis, we intravaginally infected each strain of mice with Vir3 C. albicans cells. Similarly to what was observed in the gastrointestinal infections, C57BL/6 Dectin-1–/– mice were more susceptible than wild-type mice to the infection as judged by the higher fungal burdens in the vagina (Figure 3a) and the prominent inflammatory cell recruitment in the vaginal fluids (Figure 3c, inset) and vagina. BALB/c Dectin-1–/– mice were instead more resistant to the infection than their wild-type counterparts, as judged by the decreased fungal burden (Figure 3b) and limited signs of inflammation in the vagina (Figure 3d) or of inflammatory cell recruitment in the vaginal fluid (Figure 3d, inset).
Dectin-1 promotes distinct cytokine profiles in the different mouse strains
The divergent effects of dectin-1 deficiency in C57BL/6 and BALB/c mice on susceptibility to Candida infection suggest that distinct cytokine profiles that critically define the phenotypes observed are activated following dectin-1 engagement. We measured the production of proinflammatory cytokines, such as tumor-necrosis factor (TNF)-α and IL-6, and cytokines of the IL-17 family, such as IL-17A, IL-17F and IL-17E, known to be crucial for mucosal antifungal defense,23, 24 in the stomachs of mice with gastrointestinal candidiasis. We found that the levels of TNF-α and IL-6 were higher in C57BL/6 Dectin-1–/– mice and lower in BALB/c Dectin-1–/– mice (Figure 4a) compared to the respective wild-type control. A different pattern of production was observed with members of the IL-17 family. IL-17A, IL-17F and IL-17E production was greatly reduced in C57BL/6 Dectin-1–/– mice and significantly increased in BALB/c Dectin-1–/– mice (Figure 4b) compared to the respective wild-type strains. The cytokine profiles in the vaginal fluids mirrored those in the stomach homogenates of gastrointestinally infected mice, as IL-17A, IL-17F and IL-22 were almost completely absent in C57BL/6 Dectin-1–/– mice and significantly increased in BALB/c Dectin-1–/– mice (Figure 4c) compared to the respective controls. Altogether, these findings point to similar susceptibility phenotypes to both vaginal and gastrointestinal candidiasis in the absence of dectin-1.
To further demonstrate that the different isoforms promote distinct cytokine profiles, we assessed cytokine gene expression in PPs following stimulation with β-glucan. We found that Tnfa induction was critically dependent on dectin-1, irrespective of the genetic background (Figure 5). In contrast, the expression levels of IL-12p35, IL-23p19 and Il10 were differentially affected in the absence of dectin-1. The expression of IL-23p19 was particularly reduced in PP from C57BL/6 compared to BALB/c Dectin-1–/– mice, while the expression levels of IL-12p35 and Il10 were particularly reduced in BALB/c compared to C57BL/6 Dectin-1–/– mice. Altogether, these results indicate that the impact of dectin-1 function on the cytokine response is contingent upon the genetic background and presumably upon distinct dectin-1 isoform expression.
Dectin-1 differentially impacts the Ahr/IL-22 axis in the different mouse strains
IL-22 plays a crucial role in the innate immune defense and mucosal protection from damage in mucosal candidiasis.23 Produced by NK22 cells expressing the aryl hydrocarbon receptor (AhR), IL-22 directly targets gut epithelial cells to induce signal transducer and activator of transcription 3 phosphorylation and the release of S100A8 and S100A9 peptides (known to have anti-candidal activity and anti-inflammatory effects).3, 23 We looked for Ahr expression and IL-22 production in vivo, as well as on PP cells comparatively stimulated in vitro with either β-glucan or the AhR agonist FICZ. We found that C57BL/6 Dectin-1–/– mice failed to upregulate Ahr expression and IL-22 production during infection as compared with wild-type controls (Figure 6a). In vitro, Il22 expression was not upregulated in PP from C57BL/6 Dectin-1–/– mice upon stimulation with either β-glucan or FICZ (Figure 6b). The opposite pattern of Ahr expression and IL-22 production was observed in BALB/c Dectin-1–/– mice, which showed a significant increase in Ahr expression and concomitant IL-22 production in vivo (Figure 6c) and in vitro after stimulation with FICZ (Figure 6d). These data suggest that dectin-1 signaling differentially impacts the functional activity of the AhR/IL-22 axis in gastrointestinal candidiasis.
Dectin-1 promotes distinct adaptive memory Th immune responses that are dependent on mouse genetic background
Stimulation of dectin-1 on DCs efficiently generates Th1 and Th17 responses.25 We evaluated the activation of distinct Th cell subsets in vaccine-induced resistance to C. albicans. We subjected i.g. infected mice to i.v. re-infection with the fungus 2 weeks later and evaluated the parameters of fungal growth in the kidneys and activation of CD4+ Th cells in the MLN. We found that C57BL/6 Dectin-1–/– mice were unable to resist re-infection, while wild-type C57BL/6 mice were able to resist re-infection (Figure 7a). In contrast, both wild-type and Dectin-1–/– BALB/c mice resisted the re-infection (Figure 7b). Indeed, resistance to re-infection occurred despite the high susceptibility to the primary disseminated infection exhibited by BALB/c Dectin-1–/– mice; this finding points to the ability of these mice to mount strong protective memory responses to the fungus. Similar to the above findings, intravaginally infected C57BL/6 Dectin-1–/– mice were unable to resist re-infection, in contrast to BALB/c Dectin-1–/– mice (Figure 7c and d). On assessing the quality of the Th cell responses, we found a decreased expression of Ifng and Il10 and the corresponding transcription factors Tbet and Foxp3 in the MLNs of C57BL/6 Dectin-1–/– mice compared to wild-type mice (Figure 7e). This reduction was associated with an increased expression of Il17a and Rorc (Figure 7e), suggesting that Th1 cell activation, more than Th17, is dependent on dectin-1 in C57BL/6 mice. In BALB/c Dectin-1–/– mice, resistance to re-infection was instead associated with a robust Th1/Treg response and was associated with levels of Il17a/Rorc expression that were actually lower than those of wild-type mice (Figure 7f), suggesting that Th17 cell activation, more than Th1, is dependent on dectin-1 in BALB/c mice. These results indicate that the role of Dectin-1 in shaping antifungal memory Th cell responses also depends on the genetic background of the host.
NF-κB signaling pathways are affected differently by dectin-1 deficiency, depending on the mouse strain
In addition to the classical Syk-dependent pathway leading to canonical NF-κB p65 and c-Rel subunit activation and TNF-α/IL-10 production,26 the Raf-1-dependent pathway, which inhibits the expression of the noncanonical NF-κB RelB subunits and crucially promotes Il12b transcription,13 has also been described. We assessed whether either or both of these pathways were altered in the absence of dectin-1 in DCs from C57BL/6 and BALB/c mice exposed to C. albicans. We found that the nuclear translocation of c-Rel was impaired to a greater degree in Dectin-1–/– mice in the C57BL/6 background than in the BALB/c background in response to the fungus (Figure 8a). In contrast, the nuclear translocation of RelB was increased to a higher degree in Dectin-1–/– mice in the BALB/c background than in the C57BL/6 background (Figure 8b). These findings suggest that the Syk and the Raf-1 pathways are affected differently in the absence of dectin-1 signaling in the two mouse strains.
Although the dectin-1/inflammasome host immune pathway drives protective Th17 responses and distinguishes between colonization and tissue invasion by C. albicans,27 the present study shows that the function of dectin-1 in mucosal antifungal immunity extends beyond Th17 cell activation and is critically dependent on the genetic background of the host. This phenomenon has been previously demonstrated for infections with A. fumigatus5 and Coccidioides spp.,20 in which the mechanisms of antifungal resistance were to some extent determined by the host's genetics. It has been suggested that dectin-1 responses may be dependent on the fungal strains1 and on the physical status of the β-glucans (soluble or particulate).28 Although we have obtained similar findings using two distinct C. albicans strains, we cannot rule out that these responses are also contingent upon the fungal strains. The present study is the first to show a side-by-side comparison of dectin-1 functional deficiency in mucosal candidiasis driven by a given fungal strain in genetically unrelated strains of mice. Consistent with the distinct downstream signaling pathways that are activated to regulate immunity to fungi upon dectin-1 engagement,13 we found that dectin-1 signaling is either required or dispensable in mucosal candidiasis, depending on mouse genetics. In C57BL/6 mice, dectin-1 was required for the control of fungal colonization at mucosal surfaces, both in the gastrointestinal and vaginal tracts, and was required for the production of IL-17A, IL-17F and IL-22 at sites of infection. In contrast, dectin-1 was dispensable in BALB/c mice, in which resistance to infection was associated with the production of IL-17A, IL-17F and IL-22. With respect to adaptive memory Th responses, dectin-1 was apparently required for the activation of Th1/Treg memory responses in C57BL/6 mice and for Th17 memory responses in BALB/c mice. It has been shown that dectin-1 may influence cytokine production in DCs, leading to Th1/Th17 cell activation and affecting the balance between canonical/noncanonical NF-κB activation in DCs.13 Although we found a different pattern of canonical/noncanonical NF-κB activation in DCs from each type of mouse, the exact molecular pathways linking DC activation to Th skewing during infection in the absence of dectin-1 in the different genetic backgrounds need further evaluation. Additional studies aimed at selectively inhibiting the Syk or Raf-1 pathway in the two strains of mice are required to provide the causal association between signaling pathways activated in vitro and susceptibility/resistance to infection in vivo.
It is plausible to hypothesize that these two extremely divergent phenotypes may rely on the differential expression of dectin-1 isoforms. Indeed, these alternatively spliced isoforms have been found to lead to the production of different levels of TNF upon zymosan recognition,21 suggesting that the structure of the receptor and its ability to form dimers through the stalk region may influence cytokine production. It is therefore not surprising that dectin-1 deficiency in C57BL/6 and BALB/c mice leads to disparate cytokine profiles upon mucosal infection with C. albicans. In addition and despite that no functional consequences have been observed upon zymosan recognition, nonsynonymous single nucleotide polymorphisms have been identified in C57BL/6 mice by genetic comparison with the BALB/c background,21 suggesting additional functional variability of dectin-1 between these strains. In this regard, as cooperative signaling between dectin-1 and other PRRs is crucial for efficient recognition of C. albicans cells,10 the differences in TLR2 and mannose receptor expression observed among different inbred strains of mice29, 30 may offer an additional plausible explanation.
One interesting observation of the present study is the intriguing relationship between dectin-1 and AhR. Originally recognized as causing immunosuppression after binding dioxin, mammalian AhR is now known to crucially affect IL-22 production31and the balance of T-cell differentiation into Th1/Treg vs. Th17 cells.32 In this regard, IL-22 was recently found to be produced in response to A. fumigatus by a dectin-1-dependent mechanism.33 In combination with IL-17A, IL-22 has been found to be crucially involved in the control of Candida growth in the gastrointestinal tract in conditions of Th1 and Th17 deficiency.23Moreover, vaginal epithelial cells also produced S100A8 and S100A9 following interaction with Candida,34 suggesting the possible involvement of IL-22 in vaginal candidiasis. Thus, IL-22+ cells, employing ancient effector mechanisms of immunity, may represent a primitive mechanism of resistance against the fungus under conditions of limited inflammation. The finding that the AhR/IL-22 axis was impaired in C57BL/6 Dectin-1–/– mice but not in BALB/c Dectin-1–/– mice indicates that dectin-1 receptor cooperativity may go beyond PRRs to include receptors involved in the cell cycle and metabolism.35
Regardless of the mechanisms of this cooperative signaling, our study clearly shows that dectin-1 crucially contributes to the balance of Th1/Th17/Treg CD4+ T-cell populations during infection. In contrast with what was observed in murine aspergillosis,36 dectin-1 deficiency disproportionally increases both Th1/Treg (in BALB/c mice) and Th17 (in C57BL/6 mice) cell responses after C. albicans infection, a finding showing that dectin-1 signaling can be involved in either Th1 or Th17 cell differentiation. This result may explain the relative ability of Dectin-1–/– mice in either background to eventually control the infection. However, just as BALB/c mice, more than C57BL/6 mice, showed resistance to re-infection, Th1 cells, more than Th17 cells, are endowed with long-term immune protection to the fungus, as has already been shown.23 In the early phase of the infection, however, IL-17A (and likely IL-17F) production is clearly associated with a better control of the infection at both the gastrointestinal and vaginal sites. The production of both is influenced by dectin-1. In candidiasis, the mechanisms by which dectin-1 regulates IL-17A/IL-17F production and in which innate immune cells this occurs is not known, but it is of interest that both neutrophils37 and γ-δT cells38 produce IL-17A via dectin-1.
Altogether, our data indicate that the net activity of dectin-1 in antifungal mucosal immunity is dependent on the host's genetic background and affects both the innate production of IL-17A, IL-17F and IL-22 and the regulation of the Th1/Th17/Treg balance in adaptive immunity.
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We thank Dr Cristina Massi Benedetti for the digital art and editing. The studies were supported by the Specific Targeted Research Project ‘ALLFUN’ (FP7-HEALTH-2009 contract no. 260338 to LR) and the Italian Project AIDS 2010 by ISS (Istituto Superiore di Sanità contract no. 40H40 to LR) and Fondazione Cassa di Risparmio di Perugia Project no. 2011.0124.021. AC and CC were financially supported by fellowships from Fundação para a Ciência e Tecnologia, Portugal (contracts SFRH/BPD/46292/2008 and SFRH/BD/65962/2009, respectively).
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Carvalho, A., Giovannini, G., De Luca, A. et al. Dectin-1 isoforms contribute to distinct Th1/Th17 cell activation in mucosal candidiasis. Cell Mol Immunol 9, 276–286 (2012). https://doi.org/10.1038/cmi.2012.1
- Mucosal candidiasis, Th1/Th17, Il-22, genetic background
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