Effect of Differential N-linked and O-linked Mannosylation on Recognition of Fungal Antigens by Dendritic Cells

Lam, Jennifer S.; Huang, Haibin; Levitz, Stuart M.

doi:10.1371/journal.pone.0001009

Cited by 55 publications

(44 citation statements)

References 32 publications

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“…Mannosylated fungal antigens (both N-linked and O-linked mannosylated) exhibited increased immunogenicity compared with proteins lacking mannosylation, were taken up by mannose-specific C-type lectin receptors, and colocalized in MHC class II + compartments (57). We found that deglycosylated Pep1p no longer acted as a fungal vaccine capable of activating CD4-dependent memory to the fungus (data not shown), a finding confirming the importance of MR in the rapid internalization and concentration of a variety of glycosylated fungal antigens (57).…”

Section: Discussionmentioning

confidence: 99%

CD4+ T cell vaccination overcomes defective cross-presentation of fungal antigens in a mouse model of chronic granulomatous disease

Luca¹,

Iannitti²,

Bozza³

et al. 2012

J. Clin. Invest.

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Aspergillus fumigatus is a model fungal pathogen and a common cause of infection in individuals with the primary immunodeficiency chronic granulomatous disease (CGD). Although primarily considered a deficiency of innate immunity, CGD is also linked to dysfunctional T cell reactivity. Both CD4 + and CD8 + T cells mediate vaccine-induced protection from experimental aspergillosis, but the molecular mechanisms leading to the generation of protective immunity and whether these mechanisms are dysregulated in individuals with CGD have not been determined. Here, we show that activation of either T cell subset in a mouse model of CGD is contingent upon the nature of the fungal vaccine, the involvement of distinct innate receptor signaling pathways, and the mode of antigen routing and presentation in DCs. Aspergillus conidia activated CD8 + T cells upon sorting to the Rab14 + endosomal compartment required for alternative MHC class I presentation. Cross-priming of CD8 + T cells failed to occur in mice with CGD due to defective DC endosomal alkalinization and autophagy. However, long-lasting antifungal protection and disease control were successfully achieved upon vaccination with purified fungal antigens that activated CD4 + T cells through the endosome/lysosome pathway. Our study thus indicates that distinct intracellular pathways are exploited for the priming of CD4 + and CD8 + T cells to A. fumigatus and suggests that CD4 + T cell vaccination may be able to overcome defective antifungal CD8 + T cell memory in individuals with CGD.

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Section: Discussionmentioning

confidence: 99%

CD4+ T cell vaccination overcomes defective cross-presentation of fungal antigens in a mouse model of chronic granulomatous disease

Luca¹,

Iannitti²,

Bozza³

et al. 2012

J. Clin. Invest.

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“…It has been demonstrated that recombinant glycoproteins produced by insect cells, including S2 cells, were glycosylated primarily with simple paucimannosidic N-glycans lacking sialylated antennae that prolong the half-life of glycoproteins in the blood [48][49][50]. Furthermore, it was reported that the macrophage mannose receptor specifically recognizes mannosylated proteins and degrades them through the mannose-specific C-type lectin receptor-dependent process [51]. We concluded that the lack of effectiveness of S2-produced rec-Gth administered in vivo is related to glycantargeted degradation.…”

Section: Discussionmentioning

confidence: 99%

Japanese Eel Follicle-Stimulating Hormone (Fsh) and Luteinizing Hormone (Lh): Production of Biologically Active Recombinant Fsh and Lh by Drosophila S2 Cells and Their Differential Actions on the Reproductive Biology1

Kazeto

Kohara

Miura

et al. 2008

Biology of Reproduction

128

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Two gonadotropins (Gths), follicle-stimulating hormone (Fsh) and luteinizing hormone (Lh), control gonadal steroidogenesis and gametogenesis in vertebrates, including teleost fish. Here, we report on the production of biologically active recombinant Fsh (rec-Fsh) and Lh (rec-Lh) in Japanese eel using Drosophila S2 cells. The three subunits composing Gths, i.e., glycoprotein hormone, alpha polypeptide (Cga), follicle-stimulating hormone, beta polypeptide (Fshb), and luteinizing hormone, beta polypeptide (Lhb), were at first independently produced and were proven to be glycosylated and secreted as the mature peptides. Each beta subunit, along with its Cga, was simultaneously coexpressed to produce heterodimeric rec-Fsh and rec-Lh that were subsequently highly purified. The biological activity of rec-Gths was demonstrated in various in vitro assays. The rec-Gths differentially activated their receptors, which resulted in an increase in 11-ketotestosterone (11KT) secretion, a differential alteration of gene expression of steroidogenic enzymes in immature testis, and the induction of the complete process of spermatogenesis in vitro. The data strongly suggest that Fsh and Lh differentially play important roles in the reproductive physiology of the Japanese eel. By contrast, these rec-Gths exhibited little activity in the gonad when administered in vivo. This difference between in vitro and in vivo bioactivity is probably due to the qualitative nature of glycosylation in S2 cells, which resulted in degradation of the recombinant protein in vivo. These differences in the carbohydrate moieties need to be elucidated and ameliorated.

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“…In addition to the MR, murine DCs have other C-type lectin receptors that recognize mannose residues, including DC-specific intercellular adhesion molecule 3 grabbing nonintegrin homologs, langerin and dectin-2 (28). Thus, receptor redundancy and macropinocytosis could explain the lack of difference in MP uptake between the wild-type and MR KO DCs (12,13). After antigen uptake, subsequent processing and presenting of the antigen are necessary for an adaptive immune response.…”

Section: Vol 76 2008 Susceptibility Of Mr Ko Mice To Cryptococcosismentioning

confidence: 99%

Role of the Mannose Receptor in a Murine Model ofCryptococcus neoformansInfection

et al. 2008

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Cryptococcus neoformans is an encapsulated fungal pathogen with a predilection to infect persons with suppressed T-cell function. Cryptococcal mannoproteins (MP) are highly mannosylated antigens which elicit T-cell responses in infected mice and in convalescent patients. Key to the immunogenicity of MP is its capacity to bind to the conserved mannose receptor (MR), CD206, on dendritic cells (DCs). To test the role of the MR in the immune response to C. neoformans, wild-type and MR knockout (MR KO) mice were compared by using in vivo and ex vivo models of cryptococcosis. Following a pulmonary challenge with C. neoformans, MR KO mice died significantly faster than wild-type mice and had higher lung fungal burdens after 4 weeks of infection. Uptake of MP was similar when DCs obtained from wild-type and MR KO mice were compared. Additionally, MP did not upregulate the maturation markers major histocompatibility complex class II, CD86, and CD40 in either wild-type or MR KO DCs. However, MP stimulated lymphoproliferation in CD4 ؉ T cells obtained from the peripheral lymph nodes of infected wild-type but not MR KO mice. These studies demonstrate a nonredundant role for the MR in the development of CD4 ؉ T-cell responses to MP and protection from C. neoformans.Cryptococcus neoformans is an opportunistic fungal pathogen which preferentially afflicts immunocompromised persons, particularly those with AIDS or lymphoid malignancies and recipients of immunosuppressive treatments for solid organ transplants (2). The primary site of infection is generally the lungs. While exposure is thought to be common, most immunocompetent persons are able to contain the infection. However, in the absence of effective CD4 ϩ T-cell responses, the organism can disseminate and eventually cross the blood-brain barrier to produce cryptococcal meningitis (18).The inverse correlation between CD4 ϩ T-cell function and the propensity to develop cryptococcosis has prompted investigators to search for antigens which drive the cell-mediated immune response. In this regard, a family of heavily mannosylated proteins, termed mannoproteins (MP), has been identified as immunodominant antigens in mouse models of cryptococcosis and in patients who have recovered from infection (1,16,26). MP possess serine-and threonine-rich C-terminal regions which serve as sites for extensive O-linked mannosylation. Additional mannosylation may be provided via N linkages (17). These areas of O-linked and N-linked mannosylation promote the recognition of MP by host receptors for mannose, in particular, the mannose receptor (MR, CD206) and dendritic cell (DC)-specific intercellular adhesion molecule 3 grabbing nonintegrin (CD209) (17,21). DCs are the main antigenpresenting cells responsible for the uptake, processing, and presentation of MP to CD4 ϩ T cells (21, 22). Blocking receptors for mannose with mannan or deglycosylating MP results in strongly diminished T-cell responses (21,22,32).The MR is a C-type lectin receptor which recognizes terminally mannosylated molecules (24...

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Effect of Differential N-linked and O-linked Mannosylation on Recognition of Fungal Antigens by Dendritic Cells

Cited by 55 publications

References 32 publications

CD4+ T cell vaccination overcomes defective cross-presentation of fungal antigens in a mouse model of chronic granulomatous disease

CD4+ T cell vaccination overcomes defective cross-presentation of fungal antigens in a mouse model of chronic granulomatous disease

Japanese Eel Follicle-Stimulating Hormone (Fsh) and Luteinizing Hormone (Lh): Production of Biologically Active Recombinant Fsh and Lh by Drosophila S2 Cells and Their Differential Actions on the Reproductive Biology1

Role of the Mannose Receptor in a Murine Model ofCryptococcus neoformansInfection

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