Human plasmacytoid dendritic cells mount a distinct antiviral response to virus-infected cells

Yun, Tae Jin; Igarashi, Suzu; Zhao, Haoquan; Perez, Oriana A.; Pereira, Marcus R.; Zorn, Emmanuel; Shen, Yufeng; Goodrum, Felicia; Rahman, Adeeb; Sims, Peter A.; Farber, Donna L.; Reizis, Boris

doi:10.1126/sciimmunol.abc7302

Cited by 40 publications

(41 citation statements)

References 59 publications

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“…These results were later recapitulated using SARS-CoV-2 as the stimulus ( 25 ). Using mass cytometry, it was further shown that human pDCs mount distinct, heterogenous responses dependent on the stimulus ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

Proteomic and Single-Cell Transcriptomic Dissection of Human Plasmacytoid Dendritic Cell Response to Influenza Virus

et al. 2022

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Plasmacytoid dendritic cells [pDCs] represent a rare innate immune subset uniquely endowed with the capacity to produce substantial amounts of type-I interferons. This function of pDCs is critical for effective antiviral defenses and has been implicated in autoimmunity. While IFN-I and select cytokines have been recognized as pDC secreted products, a comprehensive agnostic profiling of the pDC secretome in response to a physiologic stimulus has not been reported. We applied LC-MS/MS to catalogue the repertoire of proteins secreted by pDCs in the unperturbed condition and in response to challenge with influenza H1N1. We report the identification of a baseline pDC secretome, and the repertoire of virus-induced proteins including most type-I interferons, various cytokines, chemokines and granzyme B. Additionally, using single-cell RNA-seq [scRNA-seq], we perform multidimensional analyses of pDC transcriptional diversity immediately ex vivo and following stimulation. Our data evidence preexisting pDC heterogeneity, with subsequent highly specialized roles within the pDC population upon stimulation ranging from dedicated cytokine super-producers to cells with APC-like traits. Dynamic expression of transcription factors and surface markers characterize subclusters within activated pDCs. Integrating the proteomic and transcriptomic datasets confirms the pDC-subcluster origin of the proteins identified in the secretome. Our findings represent the most comprehensive molecular characterization of primary human pDCs at baseline, and in response to influenza virus, reported to date.

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Section: Discussionmentioning

confidence: 99%

Proteomic and Single-Cell Transcriptomic Dissection of Human Plasmacytoid Dendritic Cell Response to Influenza Virus

et al. 2022

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“…Subsequently, individual viral particles can vary in their replication efficiency inside the host, leading to differences in host cell signaling and subsequent IFN-I secretion [22,32]. Finally, a recent report showed that the recognition of live cytomegalovirus-infected cells mounted different IFN-I response dynamics in vitro in human primary plasmacytoid dendritic cells (pDCs) compared with the self-recognition of virus mimetics [33].…”

Section: Glossarymentioning

confidence: 99%

Decoding the dynamics of multilayered stochastic antiviral IFN-I responses

Eyndhoven

Singh

Tel

2021

Trends in Immunology

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responses were first recognized for their role in antiviral immunity, but it is now widely appreciated that IFN-Is have many immunomodulatory functions, influencing antitumor responses, autoimmune manifestations, and antimicrobial defenses. Given these pivotal roles, it may be surprising that multilayered stochastic events create highly heterogeneous, but tightly regulated, all-or-nothing cellular decisions. Recently, mathematical models have provided crucial insights into the stochastic nature of antiviral IFN-I responses, which we critically evaluate in this review. In this context, we emphasize the need for innovative single-cell technologies combined with mathematical models to further reveal, understand, and predict the complexity of the IFN-I system in physiological and pathological conditions that may be relevant to a plethora of diseases. From population averages to single-cell resolutionProviding a robust first line of host defense, type I interferon (IFN-I; see Glossary) responses were first recognized for their role in antiviral immunity by Isaacs and Lindemann [1]. In addition, IFN-Is are known to have numerous immunomodulatory functions that go beyond the scope of antiviral immunity, with potent roles in antitumor responses, autoimmune diseases, and microbial infections [2][3][4]. The expression and regulation of IFN-I has been extensively studied in mammals, and important molecular regulators have been characterized (Box 1;). Population-averaged measurements have generated not only a wealth of knowledge on IFN-I responses and regulation, but also contradictory results that remain hard to interpret or understand [7]. Over the past few years, an overwhelming wave of single-cell data has changed the dogma on how systemic immune responses are generated, challenging the traditional assumption that all cells of a given lineage display nearly identical behaviors upon stimulation. HighlightsThe rise of single-cell technologies has highlighted a massive degree of cellular heterogeneity during mammalian interferon (IFN)-I responses.

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“…These results were later recapitulated using SARS-CoV-2 as the stimulus (Onodi et al, 2021). Using mass cytometry, it was further shown that human pDCs mount distinct, heterogenous responses dependent on the stimulus (Yun et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Proteomic and single-cell transcriptomic dissection of human plasmacytoid dendritic cell response to influenza virus

Ghanem

Shih

Khalili

et al. 2021

Preprint

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Plasmacytoid dendritic cells [pDCs] represent a rare innate immune subset uniquely endowed with the capacity to produce substantial amounts of type-I interferons [IFN-I]. This function of pDCs is critical for effective antiviral defenses and has been implicated in autoimmunity. While IFN-I and select cytokines have been recognized as pDC secreted products, a comprehensive agnostic profiling of the pDC secretome in response to a physiologic stimulus has not been reported. We applied LC-MS/MS to catalogue the repertoire of proteins secreted by pDCs in response to challenge with live influenza H1N1. Additionally, using single-cell RNA-seq [scRNA-seq], we perform multidimensional analyses of pDC transcriptional diversification following stimulation. Our data reveal an abundance of protein species released by pDCs in addition to IFN-I, and evidence highly specialized roles within the pDC population ranging from dedicated cytokine super-producers to cells with APC-like functions. Moreover, dynamic expression of transcription factors and surface markers characterize activated pDC fates.

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Human plasmacytoid dendritic cells mount a distinct antiviral response to virus-infected cells

Cited by 40 publications

References 59 publications

Proteomic and Single-Cell Transcriptomic Dissection of Human Plasmacytoid Dendritic Cell Response to Influenza Virus

Proteomic and Single-Cell Transcriptomic Dissection of Human Plasmacytoid Dendritic Cell Response to Influenza Virus

Decoding the dynamics of multilayered stochastic antiviral IFN-I responses

Proteomic and single-cell transcriptomic dissection of human plasmacytoid dendritic cell response to influenza virus

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