title: HMGB1 Is Involved in IFN-α Production and TRAIL Expression by HIV-1-Exposed Plasmacytoid Dendritic Cells: Impact of the Crosstalk with NK Cells.
abstract: Plasmacytoid dendritic cells (pDCs) are innate sensors of viral infections and important mediators of antiviral innate immunity through their ability to produce large amounts of IFN-α. Moreover, Toll-like receptor 7 (TLR7) and 9 (TLR9) ligands, such as HIV and CpG respectively, turn pDCs into TRAIL-expressing killer pDCs able to lyse HIV-infected CD4+ T cells. NK cells can regulate antiviral immunity by modulating pDC functions, and pDC production of IFN-α as well as cell-cell contact is required to promote NK cell functions. Impaired pDC-NK cell crosstalk was reported in the setting of HIV-1 infection, but the impact of HIV-1 on TRAIL expression and innate antiviral immunity during this crosstalk is unknown. Here, we report that low concentrations of CCR5-tropic HIV-1Ba-L promote the release of pro-inflammatory cytokines such as IFN-α, TNF-α, IFN-γ and IL-12, and CCR5-interacting chemokines (MIP-1α and MIP-1β) in NK-pDCs co-cultures. At high HIV-1BaL concentrations, the addition of NK cells did not promote the release of these mediators, suggesting that once efficiently triggered by the virus, pDCs could not integrate new activating signals delivered by NK cells. However, high HIV-1BaL concentrations were required to trigger IFN-α-mediated TRAIL expression at the surface of both pDCs and NK cells during their crosstalk. Interestingly, we identified the alarmin HMGB1, released at pDC-NK cell synapse, as an essential trigger for the secretion of IFN-α and IFN-related soluble mediators during the interplay of HIV-1 exposed pDCs with NK cells. Moreover, HMGB1 was found crucial for mTRAIL translocation to the plasma membrane of both pDCs and NK cells during their crosstalk following pDC exposure to HIV-1. Data from serum analyses of circulating HMGB1, HMGB1-specific antibodies, sTRAIL and IP-10 in a cohort of 67 HIV-1+ patients argue for the in vivo relevance of these observations. Altogether, these findings identify HMGB1 as a trigger for IFN-α-mediated TRAIL expression at the surface of pDCs and NK cells, and they suggest a novel mechanism of innate control of HIV-1 infection.
authors.affiliation: Institut Pasteur, Antiviral Immunity, Biotherapy and Vaccine Unit, Infection and Epidemiology Department, Paris, France.
authors.forename: Héla
authors.initials: H
authors.lastname: Saïdi
authors.affiliation: Institut Pasteur, Antiviral Immunity, Biotherapy and Vaccine Unit, Infection and Epidemiology Department, Paris, France.
authors.forename: Marlène
authors.initials: M
authors.lastname: Bras
authors.affiliation: Institut Pasteur, Antiviral Immunity, Biotherapy and Vaccine Unit, Infection and Epidemiology Department, Paris, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Formaglio
authors.affiliation: Institut Pasteur, Antiviral Immunity, Biotherapy and Vaccine Unit, Infection and Epidemiology Department, Paris, France.
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Melki
authors.affiliation: Institut Pasteur, Antiviral Immunity, Biotherapy and Vaccine Unit, Infection and Epidemiology Department, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Charbit
authors.affiliation: Chemistry and biology, nucleoside and immunology for therapy CBNIT, CNRS, UMR8601, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris Descartes, PRES Sorbonne Paris Cité, CICB Paris, Paris, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Herbeuval
authors.affiliation: Institut Pasteur, Antiviral Immunity, Biotherapy and Vaccine Unit, Infection and Epidemiology Department, Paris, France.
authors.forename: Marie-Lise
authors.initials: ML
authors.lastname: Gougeon
mesh_terms: D000328:Adult; D002462:Cell Membrane / Q000378:metabolism; D018925:Chemokines / Q000276:immunology / Q000378:metabolism; D015331:Cohort Studies; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D024243:HMGB1 Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D016898:Interferon-alpha / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D021381:Protein Transport; D013601:T-Lymphocytes / Q000276:immunology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D055815:Young Adult
chemical_list: D018925:Chemokines; D016207:Cytokines; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D016898:Interferon-alpha; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human