Toll-Like Receptor 2 Suppresses Immunity against Candida albicans through Induction of IL-10 and Regulatory T Cells

Department of Medicine,, University Medical Center St. Radboud, Nijmegen, The Netherlands.
The Journal of Immunology (Impact Factor: 5.36). 04/2004; 172(6):3712-8. DOI: 10.4049/jimmunol.172.6.3712
Source: PubMed

ABSTRACT Toll-like receptor (TLR) 2 and TLR4 play a pivotal role in recognition of Candida albicans. We demonstrate that TLR2(-/-) mice are more resistant to disseminated Candida infection, and this is associated with increased chemotaxis and enhanced candidacidal capacity of TLR2(-/-) macrophages. Although production of the proinflammatory cytokines TNF, IL-1alpha, and IL-1beta is normal, IL-10 release is severely impaired in the TLR2(-/-) mice. This is accompanied by a 50% decrease in the CD4+CD25+ regulatory T (Treg) cell population in TLR2(-/-) mice. In vitro studies confirmed that enhanced survival of Treg cells was induced by TLR2 agonists. The deleterious role of Treg cells on the innate immune response during disseminated candidiasis was underscored by the improved resistance to this infection after depletion of Treg cells. In conclusion, C. albicans induces immunosuppression through TLR2-derived signals that mediate increased IL-10 production and survival of Treg cells. This represents a novel mechanism in the pathogenesis of fungal infections.

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Available from: Gosse J Adema, Aug 26, 2015
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    • "We were unable to detect a role for TLR-2 in TNF-␣ production by mast cells in response to C. albicans, a phenomenon previously described in murine peritoneal macrophages derived from TLR-2 knockout mice (Netea et al., 2004). However, we cannot discard that TLR-2 is activated in mast cells in response to C. albicans; it is possible that signaling through this PRR is involved in the production of other cytokines production, such as IL-10 (Netea et al., 2004). A recent study showed that mast cells were able to phagocytose C. albicans and produce ROS (Trevisan et al., 2014). "
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    ABSTRACT: Mast cells are crucial elements of the innate immune response. They reside in tissues that are commonly exposed to the external environment, such as the skin and mucosae, where they can rapidly detect the presence of pathogens and mount a potent inflammatory response that recruits other cellular effectors of the immune response. The contribution of mast cells to the immune response to viruses, bacteria, protozoa and multicellular parasites is well established, but there is scarce information about the role of these cells in fungal infections. In this study, we analyzed if mast cells are activated by Candida albicans and if the C-type lectin receptor Dectin-1 is involved in its recognition. We found that both yeasts and hyphae of C. albicans-induced mast cell degranulation and production of TNF-α, IL-6, IL-10, CCL3 and CCL4, while only yeasts were able to induce IL-1β. Mast cells also produced ROS after stimulation with both dimorphic phases of C. albicans. When mast cells were activated with yeasts and hyphae, they showed decreased expression of IκBα and increased presence of phosphorylated Syk. Blockade of the receptor Dectin-1, but not Toll-like receptor 2, decreased TNF-α production by mast cell in response to C. albicans. These results indicate that mast cells are capable of sensing the two phases of C. albicans, and suggest that mast cells participate as an early inductor of inflammation during the early innate immune response to this fungus. Copyright © 2015 Elsevier GmbH. All rights reserved.
    Immunobiology 05/2015; 220(9). DOI:10.1016/j.imbio.2015.05.005 · 3.18 Impact Factor
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    • "Certain dermatophytes like T. rubrum produce substances e.g., the mannans associated with glycoproteins that diminish the immune response thus prevent complete eradication of the fungus [26]. Some fungi other than dermatophyte genera infecting the skin can induce immune-suppression through toll like receptor 2 (TLR2) mediated IL-10 release, and this leads to generation of CD4 + CD25 + T-regulatory cells with immunosuppressive potential [27]. It is suggested that T. rubrum has the ability to suppress the expression of toll like receptors in keratinocytes and Langerhans cells in dermis and epidermis necessary for stimulation of Th1-type cell response. "
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    Current Protein and Peptide Science 05/2014; 15:437-444. · 2.33 Impact Factor
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    • "Mice lacking TLR2 exhibit an intrinsic defect in the number of CD4 + CD25 + Treg subset that maintains peripheral tolerance, but may also dampen the immune response to infection (Netea et al., 2004). Upon intravenous Candida infection, absence of Tregs results in improved fungal clearance 7 days after infection and better survival of TLR2 −/− mice when compared to wild-type mice (Bellocchio et al., 2004a; Netea et al., 2004). By contrast, in an intraperitoneal model of candidiasis, clearance is impaired 1 day afterinfection in the absence of TLR2 (Tessarolli et al., 2010). "
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    ABSTRACT: Hundred-thousands of fungal species are present in our environment, including normal colonizers that constitute part of the human microbiota. The homeostasis of host-fungus interactions encompasses efficient fungal sensing, tolerance at mucosal surfaces, as well as antifungal defenses. Decrease in host immune fitness or increase in fungal burden may favor pathologies, ranging from superficial mucocutaneous diseases to invasive life-threatening fungal infections. Toll-like receptors (TLRs) are essential players in this balance, due to their ability to control both inflammatory and anti-inflammatory processes upon recognition of fungal-specific pathogen-associated molecular patterns (PAMPs). Certain members of the TLR family participate to the initial recognition of fungal PAMPs on the cell surface, as well as inside phagosomes of innate immune cells. Active signaling cascades in phagocytes ultimately enable fungus clearance and the release of cytokines that shape and instruct other innate immune cells and the adaptive immune system. Some TLRs cooperate with other pattern recognition receptors (PRRs) (e.g., C-type lectins and Galectins), thus allowing for a tailored immune response. The spatio-temporal and physiological contributions of individual TLRs in fungal infections remains ill-defined, although in humans, TLR gene polymorphisms have been linked to increased susceptibility to fungal infections. This review focuses entirely on the role of TLRs that control the host susceptibility to environmental fungi (e.g., Aspergillus, Cryptoccocus, and Coccidoides), as well as to the most frequent human fungal pathogens represented by the commensal Candida species. The emerging roles of TLRs in modulating host tolerance to fungi, and the strategies that evolved in some of these fungi to evade or use TLR recognition to their advantage will also be discussed, as well as their potential suitability as targets in vaccine therapies.
    Frontiers in Cellular and Infection Microbiology 11/2012; 2:142. DOI:10.3389/fcimb.2012.00142 · 2.62 Impact Factor
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