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Differential activity of type I interferon subtypes for dendritic cell differentiation.

ABSTRACT: The type I interferon (IFN) family comprises 15 cytokines (in human 13?, 1?, 1?), which exert several cellular functions through binding to a common receptor. Despite initial activation of the same Jak/Stat signalling pathway, the cellular response may differ depending on type I IFN subtype. We investigated the activity of six type I IFN subtypes - IFN?1, ?2, ?8, ?21, ? and ?- to promote the differentiation of dendritic cells (DC). Transcriptome analyses identified two distinct groups, the IFN?/?-DC and the IFN?-DC. In addition, the expression level of seven chemokines and several cell surface markers characteristic of DC distinguished IFN?-DC and IFN?-DC. These differences are unlikely to impact the efficacy of T cell functional response since IFN?2-DC and IFN?-DC were equipotent in inducing the proliferation and the polarization of allogenic naïve CD4 T cells into Th1 cells and in stimulating autologous antigen specific CD4 or CD8 T cells. Of the functional parameters analysed, the only one that showed a modest differential was the phagocytic uptake of dead cells which was higher for IFN?2-DC.

SUBMITTER: Garcin G

PROVIDER: S-EPMC3589429 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Differential activity of type I interferon subtypes for dendritic cell differentiation.

Garcin Geneviève G Bordat Yann Y Chuchana Paul P Monneron Danièle D Law Helen K W HK Piehler Jacob J Uzé Gilles G

PloS one 20130305 3

The type I interferon (IFN) family comprises 15 cytokines (in human 13α, 1β, 1ω), which exert several cellular functions through binding to a common receptor. Despite initial activation of the same Jak/Stat signalling pathway, the cellular response may differ depending on type I IFN subtype. We investigated the activity of six type I IFN subtypes - IFNα1, α2, α8, α21, ω and β- to promote the differentiation of dendritic cells (DC). Transcriptome analyses identified two distinct groups, the IFNα/ ...[more]

PMID: 23472200

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Project description:SARS-CoV-2 fine-tunes the interferon (IFN)-induced antiviral responses, which play a key role in preventing coronavirus disease 2019 (COVID-19) progression. Indeed, critically ill patients show an impaired type I IFN response accompanied by elevated inflammatory cytokine and chemokine levels, responsible for cell and tissue damage and associated multi-organ failure. Here, the early interaction between SARS-CoV-2 and immune cells was investigated by interrogating an in vitro human peripheral blood mononuclear cell (PBMC)-based experimental model. We found that, even in absence of a productive viral replication, the virus mediates a vigorous TLR7/8-dependent production of both type I and III IFNs and inflammatory cytokines and chemokines, known to contribute to the cytokine storm observed in COVID-19. Interestingly, we observed how virus-induced type I IFN secreted by PBMC enhances anti-viral response in infected lung epithelial cells, thus, inhibiting viral replication. This type I IFN was released by plasmacytoid dendritic cells (pDC) via an ACE-2-indipendent but Neuropilin-1-dependent mechanism. Viral sensing regulates pDC phenotype by inducing cell surface expression of PD-L1 marker, a feature of type I IFN producing cells. Coherently to what observed in vitro, asymptomatic SARS-CoV-2 infected subjects displayed a similar pDC phenotype associated to a very high serum type I IFN level and induction of anti-viral IFN-stimulated genes in PBMC. Conversely, hospitalized patients with severe COVID-19 display very low frequency of circulating pDC with an inflammatory phenotype and high levels of chemokines and pro-inflammatory cytokines in serum. This study further shed light on the early events resulting from the interaction between SARS-CoV-2 and immune cells occurring in vitro and confirmed ex vivo. These observations can improve our understanding on the contribution of pDC/type I IFN axis in the regulation of the anti-viral state in asymptomatic and severe COVID-19 patients.

Project description:Interferons (IFNs) play a crucial role in the host's immune response and other homeostatic control actions. Three IFN types and several IFN families within the types allow for a plethora of regulatory actions. The number of distinct IFN molecules is highest among type I IFNs and, in particular, within the IFN-? family. In pigs, there are 17 IFN-? subtypes with different antiviral activities and different expression profiles; however, no data are available about biological properties other than the antiviral effector activities. Therefore, 16 porcine IFN-? genes were cloned, expressed in mammalian Chinese hamster ovary cells, and characterized for antiviral, anti-inflammatory, and MHC-modulating activities at a pre-established level of 10?IU/mL. Antiviral activity: IFN-?2, -?5, -?9, and -?10 showed the highest level of activity in a pseudorabies virus yield reduction assay. On the contrary, little, if any, activity was shown by IFN-?3, -?7, -?13, -?4, and -?15. Anti-inflammatory activity: With the exception of IFNs-?2, -?7, -?9, and -?11, all IFN-? subtypes had significant anti-inflammatory control activity in an interleukin-8 (IL-8) yield reduction assay. Gene expression analyses showed that some IFN-? subtypes can significantly downregulate the expression of IL-8, tumor necrosis factor ? (TNF-?), IL-6, Toll-like receptor 4 (TLR4), ?D1, and nuclear factor-?B (NF-kB) genes, while maintaining or upregulating the expression of ?D4. Immunomodulation: A significant upregulation of class I and/or class II MHC was induced by all the IFNs under study, with the exception of IFNs-?11, -?15, and -?16, which instead significantly downregulated class I MHC. Our results indicate that gene duplications in the porcine IFN-? family underlie diverse effector and regulatory activities, being therefore instrumental in host survival and environmental adaptation. This role of IFN-? could be founded on fine-tuning and regulation of pro- and anti-inflammatory control actions after exposure to both infectious and noninfectious environmental stressors.

Project description:The immune response against cancer generated by type-I-interferons (IFN-1) has recently been described. Exogenous and endogenous IFN-?/? have an important role in immune surveillance and control of tumor development. In addition, IFN-1s have recently emerged as novel DAMPs for the consecutive events connecting innate and adaptive immunity, and they also have been postulated as an essential requirement for induction of immunogenic cell death (ICD). In this context, photodynamic therapy (PDT) has been previously linked to the ICD. PDT consists in the administration of a photosensitizer (PS) and its activation by irradiation of the affected area with visible light producing excitation of the PS. This leads to the local generation of harmful reactive oxygen species (ROS) with limited or no systemic defects. In the current work, Me-ALA inducing PpIX (endogenous PS) was administrated to B16-OVA melanoma cells. PpIX preferentially localized in the endoplasmic reticulum (ER). Subsequent PpIX activation with visible light significantly induced oxidative ER-stress mediated-apoptotic cell death. Under these conditions, the present study was the first to report the in vitro upregulation of IFN-1 expression in response to photodynamic treatment in melanoma. This IFN-?/? transcripts upregulation was concurrent with IRF-3 phosphorylation at levels that efficiently activated STAT1 and increased ligand receptor (cGAS) and ISG (CXCL10, MX1, ISG15) expression. The IFN-1 pathway has been identified as a critical molecular pathway for the antitumor host immune response, more specifically for the dendritic cells (DCs) functions. In this sense, PDT-treated melanoma cells induced IFN-1-dependent phenotypic maturation of monocyte-derived dendritic cells (DCs) by enhancing co-stimulatory signals (CD80, MHC-II) and tumor-directed chemotaxis. Collectively, our findings showed a new effect of PDT-treated cancer cells by modulating the IFN-1 pathway and its impact on the activation of DCs, emphasizing the potential relevance of PDT in adoptive immunotherapy protocols.

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Differential activity of type I interferon subtypes for dendritic cell differentiation.

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Differential activity of type I interferon subtypes for dendritic cell differentiation.

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