Cross‐presentation, dendritic cell subsets, and the generation of immunity to cellular antigens

Heath, William R.; Belz, Gabrielle T.; Behrens, Georg M. N.; Smith, Christopher M.; Forehan, Simon; Parish, Ian A.; Davey, Gayle M.; Wilson, Nicholas S.; Carbone, Federico; Villadangos, José A

doi:10.1111/j.0105-2896.2004.00142.x

Cited by 645 publications

(560 citation statements)

References 148 publications

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“…Murine splenic CD11c + DC can be divided into different subsets, based on the differential expression of CD4, CD8 and other phenotypic markers, and it has been proposed that DC subsets have specialized functions in the induction and regulation of immunity and tolerance [32]. Recently, CD8 + DC in the T cell areas of the spleen have been shown to preferentially activate CD8 + T cells, while CD8 -DC, which are located in the marginal zone of the spleen, are more efficient in MHC class II presentation and activation of CD4 + T cells [33,34].…”

Section: Introductionmentioning

confidence: 99%

CD8^– dendritic cells preferentially cross‐present Saccharomyces cerevisiae antigens

et al. 2008

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Mouse splenic dendritic cell (DC) subsets possess distinct antigen-presentation abilities. CD8 + DC are specialized in cross-presentation of antigens to CD8 + T cells, whereas CD8 -DC are more efficient in antigen presentation to CD4 + T cells. In this study, we examined the capacity of CD8 + and CD8 -DC subsets to present fungal antigens in MHC class I and II molecules to CD8 + and CD4 + T cells, respectively. We used ovalbuminexpressing Saccharomyces cerevisiae (yeast-OVA) as a fungal model system. Both CD8 + and CD8 -DC subsets phagocytosed yeast in equal amounts and uptake was mediated via dectin-1. In addition, both DC subsets induced similar OVA-specific CD4 + T cell proliferation after incubation with yeast-OVA. However, the induction of OVA-specific CD8 + T cell activation was largely restricted to the CD8 -DC subset. Furthermore, only CD8 -DC produced cytokines such as IL-10 and TNF-a and increased IL-23p19 and IL-23p40 mRNA levels in response to yeast. Our results strongly suggest that DC subsets have different functions in the elicitation of adaptive immune responses in vivo. IntroductionFungal infections with pathogenic yeasts such as Candida albicans, Aspergillus fumigatus, Histoplasma capsulatum and Cryptococcus neoformans are a major problem in immunocompromised persons. These opportunistic pathogens usually do not pose problems in healthy individuals, but frequently become invasive in patients suffering from HIV, patients with malignancies or transplant recipients, resulting in life-threatening diseases [1][2][3].Both innate and adaptive immune responses are essential to induce protection against fungi. Dendritic cells (DC) play a central role in the adaptive immune response by capturing fungi and presenting their antigens in major histocompatibility complex (MHC) class I and MHC class II molecules to T cells [4, 5]. DC express a panel of microbial recognition receptors such as Toll-like receptors (TLR) and C-type lectin receptors that are essential for the elicitation of adaptive immune responses [6]. Of these receptors, TLR2 and the DCassociated C-type lectin (dectin-1) are specifically involved in recognition of fungal components [7][8][9]. Zymosan and fungal pathogens like C. albicans and A. fumigatus are sensed by TLR2 that signals via myeloid differentiation factor 88 (MyD88), resulting in NF-jB activation and the production of cytokines [10][11][12][13]. The importance of this signaling cascade can be inferred from the fact that MyD88-knockout mice show an increased susceptibility to fungal infections [14,15].Dectin-1 is expressed on myeloid cells like macrophages, neutrophils, monocytes, and even a subset of T cells [16]. Dectin-1 mediates fungal recognition and Revised 2/11/07 Accepted 11/12/07 [DOI 10.1002/eji.200737647] Key words: Antigen presentation Á Dendritic cell Á Fungal Á T cell Abbreviations: b2m: b2-microglobulin Á Dectin-1: DC-associated C-type lectin-1 Á CR3: complement receptor 3 Á MR: mannose receptor Á SIGNR1: ICAM-3-grabbing nonintegrin (DC-SIGN) homolog, SIGN-related...

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Section: Introductionmentioning

confidence: 99%

CD8^– dendritic cells preferentially cross‐present Saccharomyces cerevisiae antigens

et al. 2008

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“…[21][22][23] It was proposed that dying antigen-expressing somatic cells would become attractive targets for infiltrating local DCs and presenting to CD8+ T cells through crosspriming. 24 It raises a possibility that delivery of Bcl-xl DNA into antigen-expressing somatic cells may limit antigen resources especially in crosspriming, which is critical in inducing antigen-specific CD8+ T-cell responses. Additionally, overexpression of Bcl-xl may contribute to tumorgensis in vivo.…”

Section: Introductionmentioning

confidence: 99%

‘Survival gene’ Bcl-xl potentiates DNA-raised antitumor immunity

et al. 2005

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T-cell priming is strongly affected by the longevity of antigenbearing dendritic cells (DCs), which are typically short-lived in lymphoid tissues. 'Survival gene' Bcl-xl is critical for the lifespan of DCs in vivo. Here, we showed that in vivo coadministration of Bcl-xl under control of the DC-specific promoter (CD11c-Bcl-xl) and TRP2hsp70 DNA prolonged T-cell stimulation by DCs and augmented TRP2-specific-IFNg-producing CD8+ T-cell responses. Consistent with these findings, enhanced protection and significant therapeutic immunity to B16 melanoma was generated by this coimmunization strategy, which also augmented therapeutic immunity to GL-26 tumor. In this B16 melanoma model, results from animal experiments with depletion of immune cells indicate that CD8+ T cells and NK cells are important in the antitumor immunity induced by this coimmunization strategy. These observations suggest that 'survival gene' Bcl-xl potentiates the magnitude of antigen-specific-CD8+ T-cell responses and the efficacy of antitumor immunity induced by DNA vaccine, and is relevant for the design of in vivo targeted DC-based vaccine strategies to improve immunity against cancer. Gene Therapy (2005) 12, 1517-1525.

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“…We investigated the ability of PC7A NP on cytosolic delivery and cross-presentation of antigens 13 . Incubation of OVA-PC7A NP with bone marrow derived dendritic cells (BMDCs) showed similar amount of antigen uptake compared to OVA-PD5A NP and less than the OVA only group (Fig.…”

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confidence: 99%

A STING-activating nanovaccine for cancer immunotherapy

et al. 2017

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Generation of tumor-specific T cells is critically important for cancer immunotherapy1,2. A major challenge in achieving a robust T cell response is the spatio-temporal orchestration of antigen cross-presentation in antigen presenting cells (APCs) with innate stimulation. Here we report a minimalist nanovaccine by a simple physical mixture of an antigen with a synthetic polymeric nanoparticle, PC7A NP, which generated a strong cytotoxic T cell response with low systemic cytokine expression. Mechanistically, PC7A NP achieved efficient cytosolic delivery of tumor antigens to APCs in draining lymph nodes leading to increased surface presentation while simultaneously activating type I interferon-stimulated genes. This effect was dependent on STING but not Toll-like receptor or MAVS pathway. Nanovaccine produced potent tumor growth inhibition in melanoma, colon cancer, and human papilloma virus-E6/E7 tumor models. Combination of PC7A nanovaccine with an anti-PD-1 antibody showed great synergy with 100% survival over 60 days in a TC-1 tumor model. Rechallenging of these tumor-free animals with TC-1 cells led to complete inhibition of tumor growth, suggesting generation of long-term antitumor memory. The STING-activating nanovaccine offers a simple, safe and robust strategy in boosting anti-tumor immunity for cancer immunotherapy.

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Cross‐presentation, dendritic cell subsets, and the generation of immunity to cellular antigens

Cited by 645 publications

References 148 publications

CD8^– dendritic cells preferentially cross‐present Saccharomyces cerevisiae antigens

CD8^– dendritic cells preferentially cross‐present Saccharomyces cerevisiae antigens

‘Survival gene’ Bcl-xl potentiates DNA-raised antitumor immunity

A STING-activating nanovaccine for cancer immunotherapy

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Cross‐presentation, dendritic cell subsets, and the generation of immunity to cellular antigens

Cited by 645 publications

References 148 publications

CD8– dendritic cells preferentially cross‐present Saccharomyces cerevisiae antigens

CD8– dendritic cells preferentially cross‐present Saccharomyces cerevisiae antigens

‘Survival gene’ Bcl-xl potentiates DNA-raised antitumor immunity

A STING-activating nanovaccine for cancer immunotherapy

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Resources

About

CD8^– dendritic cells preferentially cross‐present Saccharomyces cerevisiae antigens

CD8^– dendritic cells preferentially cross‐present Saccharomyces cerevisiae antigens