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Single cell transcriptomic atlas of human plasmacytoid dendritic cells reveals a distinct cytotoxic-like subset in HIV-1 infected individuals.

ABSTRACT: To understand how the transcriptome of pDCs is impacted by HIV-1 infection and exogenous stimulation, we sorted pDCs from people with HIV-1 (PWH) on antiretroviral treatment before and after toll-like receptor 9 (TLR9) agonist treatment, as well as from healthy controls, and performed single-cell (sc)-RNA sequencing. We generated a transcriptomic atlas of over 112,000 pDCs. Our cluster analysis revealed an inducible cytotoxic-like pDC cluster characterized by high expression of both antiviral and cytotoxic genes. We further reported that this cytotoxic-like pDC cluster is distinct from NK and T cells. This observation was further supported by our cell-cell communication analysis revealing that cytotoxic-like pDCs exhibit similar incoming and outgoing cellular communicating signals as other pDCs. In addition to the cytotoxic-like pDC cluster, we also characterized two homogenous pDC clusters (pDC1 and pDC2) and an exhausted pDC cluster. In conclusion, our findings provide a comprehensive pDC transcriptomic atlas and open a new scope on the mechanisms of regulation and function of cytotoxic-like pDCs in HIV and other infections.

ORGANISM(S): Homo sapiens

PROVIDER: GSE228078 | GEO | 2023/09/05

REPOSITORIES: GEO

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Project description:To identify potential dysregulation of miRNA expression in plasmacytoid dendritic cells from Systemic Sclerosis patients (SSc), miRNA profiling was performed in pDCs from healthy donors or patients with the most severe fibrotic cutaneous form of SSc, namely in dcSSc, with either disease duration shorter (edcSSc) or longer than two years (ldcSSc). Plasmacytoid dendritic cells (pDCs) are a critical source of type I interferons (IFNs) that can contribute to the onset and maintenance of autoimmunity. Molecular mechanisms leading to pDC dysregulation and persistent type I IFN signature are largely unexplored, especially in systemic sclerosis (SSc), a disease in which pDCs infiltrate fibrotic skin lesions and produce higher levels of IFNa as compared to healthy controls. To investigate potential microRNA–mediated epigenetic mechanisms underlying pDC dysregulation and type I IFN production in SSc. microRNA expression profiling and validation was performed in highly purified pDCs obtained from the peripheral blood of 3 independent cohorts of healthy controls and SSc patients. Possible functions of miR-618 on pDC biology were identified by overexpression in healthy pDCs. miR-618 expression was upregulated in pDCs of SSc patients, including those in the early stage of disease onset and not presenting with skin fibrosis. IRF8, a crucial transcription factor for pDC development and activation, was identified as a target of miR-618. miR-618 overexpression reduced the development of pDCs from CD34+ cells in-vitro and enhanced their ability to secrete IFNα, mimicking the pDC phenotype observed in SSc patients. miR-618 upregulation suppresses pDC development and increases their ability to secrete IFNα, potentially contributing to the type I IFN signature observed in SSc patients. Considering the importance of pDCs in the pathogenesis of SSc and other diseases characterized by a type I IFN signature, miR-618 potentially represents an important epigenetic target to regulate immune system homeostasis in these conditions.

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Single cell transcriptomic atlas of human plasmacytoid dendritic cells reveals a distinct cytotoxic-like subset in HIV-1 infected individuals.

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