Adaptive Immunity to Fungi

Verma, Akash; Wüthrich, Marcel; Deepe, George S.; Klein, Bruce S.

doi:10.1101/cshperspect.a019612

Cited by 84 publications

(80 citation statements)

References 215 publications

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“…As a link between innate and adaptive immunity, dendritic cells (DCs) have an inherent role in regulating immunity through their ability to influence initial T cell responses [6] to a wide array of antigenic stimuli including those originating from fungi and other pathogens, tissue grafts, and cancerous cells. Factors broadly influencing the outcome of DC: T cell interactions include the origin of the antigen and the antigenic load; evidence suggests a low antigenic load contributes to Th2 immunity whereas a high antigenic load promotes Th1 responses [13].…”

Section: Immunoregulatory Cellsmentioning

confidence: 99%

“…Sterilizing immunity against fungal pathogens most strongly correlates with the development of “inflammatory” DCs (or “DC1”), Th1 and Th17 immune responses and the subsequent classical activation of effector macrophages (or “M1”) (Figure 1, pathway 1) [6,7,8]. In contrast, many fungal infections prove difficult to eradicate and provoke “immunomodulatory” DC (or “DC2”), Th2 and T regulatory (Treg) responses, and local alternative macrophage activation (or “M2”) with resultant persistent infection (Figure 1, pathway 2) [9,10,11,12].…”

Section: Introductionmentioning

confidence: 99%

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Immunoregulation in Fungal Diseases

2016

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This review addresses specific regulatory mechanisms involved in the host immune response to fungal organisms. We focus on key cells and regulatory pathways involved in these responses, including a brief overview of their broader function preceding a discussion of their specific relevance to fungal disease. Important cell types discussed include dendritic cells and regulatory T cells, with a focus on specific studies relating to their effects on immune responses to fungi. We highlight the interleukin-10, programmed cell death 1, and cytotoxic T lymphocyte-associated protein 4 signaling pathways and emphasize interrelationships between these pathways and the regulatory functions of dendritic cells and regulatory T cells. Throughout our discussion, we identify selected studies best illustrating the role of these cells and pathways in response to specific fungal pathogens to provide a contextual understanding of the tightly-controlled network of regulatory mechanisms critical to determining the outcome of exposure to fungal pathogens. Lastly, we discuss two unique phenomena relating to immunoregulation, protective tolerance and immune reactivation inflammatory syndrome. These two clinically-relevant conditions provide perspective as to the range of immunoregulatory mechanisms active in response to fungi.

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Section: Immunoregulatory Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immunoregulation in Fungal Diseases

2016

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“…More recent studies have shown that antibody-or cytokine-mediated disruption of Th1 immunity or Th2-favoring interventions correlate with adverse outcomes in murine fungal infection models (5, 9). The discovery of Th17 and regulatory T cells (Tregs), the development of CD4 + T cell receptor-transgenic mice (114)(115)(116), the identification of fungal epitopes that elicit antigen-specific responses (117)(118)(119), and the precise phenotyping of PIDD patients with mycoses have advanced insight into CD4 + T cell-driven antifungal immunity (120). At the site of infection, fungal cells and antigens are internalized by tissue-resident DC subsets and monocyte-derived cells (Mo-DCs).…”

Section: Il-17mentioning

confidence: 99%

Immunity against fungi

Lionakis¹,

Iliev²,

Hohl³

2017

JCI Insight

106

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“…CLRs expressed on antigen-presenting cells recognize carbohydrate structures on the fungal cell wall and tailor adaptive responses via the instruction of CD4 ϩ T helper cells (1,8,9). In a murine model of subcutaneous vaccination, we have previously uncovered an essential role of Dectin-2 in inducing antifungal immunity and CD4 ϩ T cell development (10).…”

mentioning

confidence: 99%

The C-Type Lectin Receptor MCL Mediates Vaccine-Induced Immunity against Infection with Blastomyces dermatitidis

Wang

Klein

et al. 2016

Infect Immun

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Vaccination is one of the greatest achievements in medicine and a powerful tool to protect humans against infectious diseases. The current armamentarium and efficacy of antifungal drugs is limited; thus, fungal vaccines are urgently needed (1). Today's vaccines against infectious diseases preferentially induce protective antibodies, driven by adjuvants such as alum, which has been used in a clinical trial of vaccination against Candida albicans with a recombinant fungal antigen (2). However, accumulating evidence suggests that antibodies contribute less to antifungal host defense than cellular immunity, which is required to resolve most fungal infections (3-5). Vaccine-induced resistance to fungi requires CD4 ϩ T cells that produce the proinflammatory cytokines interleukin-17 (IL-17; Th17 cells) and gamma interferon (IFN-␥; Th1 cells) (3, 4). While Th1 cells may be dispensable for vaccineinduced immunity against infection with systemic dimorphic fungi in murine models, Th17 cells generally are required for resistance against these infections (3). Hence, the identification of host pathogen recognition receptors (PRR) and signaling pathways that lead to the induction of vaccine-induced Th17 cell responses is critical for the rational design of antifungal vaccines.C-type lectin receptors (CLRs) represent a large family of PRRs that share structurally homologous carbohydrate recognition domain(s) (CRD) (6, 7). CLRs expressed on antigen-presenting cells recognize carbohydrate structures on the fungal cell wall and tailor adaptive responses via the instruction of CD4 ϩ T helper cells (1,8,9). In a murine model of subcutaneous vaccination, we have previously uncovered an essential role of Dectin-2 in inducing antifungal immunity and CD4 ϩ T cell development (10). Using a reporter cell assay, we showed that Dectin-2 directly binds to vaccine yeast and triggers downstream NFAT signaling. Animals lacking Dectin-2 or its adaptor, FcR␥, fail to differentiate and recruit Th1/Th17 cells to the lung upon recall, and consequently the mice lack the ability to acquire vaccine-induced resistance.MCL (also known as Dectin-3, CLECSF8, and CLEC4D) is a recently described Dectin-2 family member (11). It was originally cloned from macrophages (12) and later found to be expressed in other myeloid cell types, including monocytes and various subsets of dendritic cells (13,14). Like Dectin-2, MCL is a type II transmembrane protein with a single extracellular CRD, and it associates with FcR␥ to trigger intracellular signaling (15). Recent studies have shown that MCL recognizes mycobacterial cord factor TDM (trehalose-6,6=-dimycolate) (15, 16), a glycolipid ligand also recognized by another Dectin-2 family member, Mincle. MCL recognition of TDM induces Mincle expression and thus enhances host innate responses (15,17,18). Moreover, MCL is able to form a receptor complex with Mincle (19-21) to facilitate surface expression of the latter (19). Consequently, MCL is critically involved in TDM-induced experimental autoimmune encephalomyelitis (EAE...

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Adaptive Immunity to Fungi

Cited by 84 publications

References 215 publications

Immunoregulation in Fungal Diseases

Immunoregulation in Fungal Diseases

Immunity against fungi

The C-Type Lectin Receptor MCL Mediates Vaccine-Induced Immunity against Infection with Blastomyces dermatitidis

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