Hepatitis B Virus Blocks the CRE/CREB Complex and Prevents TLR9 Transcription and Function in Human B Cells.
J Immunol. 2018 Sep 5.
Tout I, Gomes M, Ainouze M, Marotel M, Pecoul T, Durantel D, Vaccarella S, Dubois B, Loustaud-Ratti V, Walzer T, Alain S, Chemin I, Hasan U
Découvrez l’équipe de Thierry Walzer Immunité Innée dans les maladies infectieuses et autoimmunes.
Effective B cell responses such as cytokine secretion, proliferation, and Ab-specific responses are essential to clear hepatitis B virus (HBV) infection. However, HBV alters numerous immune pathways to persist in the host. B cell activity depends on activation of the innate sensor TLR9 by viral or bacterial DNA motifs. How HBV can deregulate B cell functions remains unknown. In this study, we show that HBV can enter and decrease TLR9 expression in human primary B cells. Using PBMCs from human blood donors, we show that TLR9 expression was reduced in all peripheral B cells subsets exposed to HBV. B cell function mediated by TLR9, but not TLR7, such as proliferation and proinflammatory cytokines secretion, were abrogated in the presence of HBV; however, global Ig secretion was not downregulated. Mechanistically, we show, using human myeloma B cell line RPMI 8226, that the surface Ag hepatitis B surface Ag was responsible for TLR9 dysfunction. hepatitis B surface Ag suppressed the phosphorylation and thus the activation of the transcription factor CREB, preventing TLR9 promoter activity. Finally, we corroborated our in vitro findings in a cohort of chronic HBV carriers and found that TLR9 expression and function were significantly suppressed. The effect of HBV on TLR9 activity in B cells gives insights into oncoviral immune escape strategies, providing knowledge to develop novel immunotherapeutic approaches in chronic HBV-carrier patients. Copyright © 2018 by The American Association of Immunologists, Inc. DOI: 10.4049/jimmunol.1701726 PMID: 30185518
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Affiliations des auteurs:
Tout I(1), Gomes M(2), Ainouze M(1), Marotel M(1), Pecoul T(1), Durantel D(3), Vaccarella S(4), Dubois B(3), Loustaud-Ratti V(2), Walzer T(1), Alain S(2), Chemin I(3), Hasan U(1) Author information:
(1) Centre International de Recherche en Infectiologie, INSERM, U1111, 69007 Lyon,France; Université Claude Bernard Lyon 1, 69100 Lyon, France; CNRS, UMR5308, 69100 Lyon, France; École Normale Supérieure de Lyon, Université Lyon, 69007 Lyon, France.Hospices Civils de Lyon, 69495 Lyon, France. (2)Centre Hospitalier Universitaire Dupuytren, 87042 Limoges, France. (3)Cancer Research Center of Lyon, INSERM U1052-CNRS UMR5286, 69373 Lyon, France; (4)International Agency for Research on Cancer, 69372 Lyon Cedex 08, France.
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