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    Sex bias in TLR7-dependent responses: A Dosage Affair

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    Seminar Institut Cochin

    Thursday 23 May 2019 - 12:00 - Room conference Rosalind Franklin, 2nd floor

     


    Jean-Charles Guéry



    Centre de Physiopathologie de Tousouse-Purpan,
    INSERM UMR1013, CNRS UMR5282, Toulouse

     

     invited by Anne Hosmalin & Julie Chaumeil

    Institut Cochin, 22 rue Méchain, 75014 Paris

     

    Abstract

     Toll-like receptor 7 (TLR7), an endosomal sensor of exogenous and autologous single-stranded RNA, is critical to the induction of antiviral immunity, but TLR7 dosage is also a key pathogenic factor in systemic lupus erythematosus (SLE), an autoimmune disease with strong female bias. In plasmacytoid dendritic cells (pDCs), TLR7 engagement elicits strong type I interferon (IFN) production and is critical to the induction of antiviral immune responses. TLR7 is also an essential component of the germinal center response against RNA viruses. The TLR7-driven production of type I IFNs by pDCs exhibits a strong female bias, due to the combined action of estrogen-signaling and X-chromosome dosage. TLR7 is encoded by an X-linked gene, and we showed recently that this locus escapes X chromosome inactivation (XCI) in immune cells from women (46,XX) and Klinefelter syndrome males (47,XXY). In parallel, we have shown that a frequent single nucleotide polymorphism of TLR7 leads to a sex-dependent phenotype. In both studies, we observed female-specific increases in TLR7 protein expression associated with enhanced cell function in particular immune compartments, namely in B lymphocytes through XCI escape, and in plasmacytoid dendritic cells through a sex-genotype interaction. In addition, our results suggest that higher TLR7 dosage arising from XCI escape connects the presence of two X chromosomes with the increased risk of developing SLE in women and Klinefelter syndrome males.

     

    Some publications

    • Souyris M, Cenac C, Azar P, Daviaud D, Canivet A, Grunenwald S, Pienkowski C, Chaumeil J, Mejia JE, and Guéry JC. TLR7 escapes from X chromosome inactivation in immune cells. Sci. Immunol. 2018 Jan 26;3(19). pii: eaap8855. doi: 10.1126/sciimmunol.aap8855
    • Laffont S, Blanquart E, Savignac M, Cénac C, Laverny G, Metzger D, Girard JP, Belz GT, Pelletier L, Seillet C, Guéry JC. Androgen signaling negatively controls group 2 innate lymphoid cells. J Exp Med. 2017 Jun 5;214(6):1581-1592. doi: 10.1084/jem.20161807. Epub 2017 May 8.
    • Laffont S, Seillet C, Guéry JC. Estrogen Receptor-Dependent Regulation of Dendritic Cell Development and Function. Front Immunol. 2017 Feb 10;8:108. doi: 10.3389/fimmu.2017.00108. eCollection 2017. Review.
    • Laffont S, Rouquié N, Seillet C, Plumas J, Aspord C, Guéry JC. Estrogen receptor signaling and X-chromosome complement both independently contribute to the enhanced TLR-7-mediated responses of plasmacytoid dendritic cells from women. J. Immunol. 2014 Dec 1;193(11):5444-52.
    • Seillet C, Laffont S, Trémollières F, Rouquié N, Ribot C, Arnal JF, Douin-Echinard V, Gourdy P, JC Guéry. The TLR-mediated response of plasmacytoid dendritic cells is positively regulated by estradiol in vivo through cell-intrinsic estrogen receptor alpha-signaling. Blood. 2012 Jan 12;119(2):454-64.

     

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