title: Retroviral vectors induce epigenetic chromatin modifications and IL-10 production in transduced B cells via activation of toll-like receptor 2.
abstract: The immune response toward viral vectors used for gene therapy and genetic vaccination appears to be critically important in determining the therapeutic outcome. However, the mechanisms that control the immune response following gene transfer are poorly understood. Unexpectedly, we found that integrating retroviral vector particles induce stable interleukin-10 (IL-10) production in murine (BALB/c H-2(d)) transduced B cells. This requires a novel mechanism whereby the interaction of retroviral vector particle with its cognate cellular receptor activates intracellular signaling pathways resulting in stable epigenetic modifications. Murine B cells exposed to retroviral vector particles triggered the colocalization of the retroviral cellular receptor [mouse cationic amino acid transporter 1 (mCAT1)] and Toll-like receptor 2 (TLR2) into lipid microrafts, which in turn activated TLR2 signaling pathways. TLR2 activation induced STAT3 phosphorylation and increased phosphorylated histone 3 (H3) at the STAT3-binding site of the IL-10 promoter. In addition, TLR2 activation during transduction activates nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor, α (NFKBIA), thereby preventing the translocation of the nuclear factor-κB (NF-κB) complex to the nucleus and the transcription of proinflammatory cytokines. These findings open new perspectives for controlling immune responses following gene therapy and genetic vaccination.
authors.affiliation: Department of Molecular and Cellular Medicine, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.
authors.forename: Roxana R
authors.initials: RR
authors.lastname: Ahangarani
authors.forename: Wim
authors.initials: W
authors.lastname: Janssens
authors.forename: Vincent
authors.initials: V
authors.lastname: Carlier
authors.forename: Luc
authors.initials: L
authors.lastname: Vanderelst
authors.forename: Thierry
authors.initials: T
authors.lastname: Vandendriessche
authors.forename: Marinee
authors.initials: M
authors.lastname: Chuah
authors.forename: Marc
authors.initials: M
authors.lastname: Jacquemin
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Saint-Remy
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D015153:Blotting, Western; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D002843:Chromatin; D050796:STAT3 Transcription Factor; D050916:TRPV Cation Channels; D051195:Toll-Like Receptor 2; C446923:Trpv6 protein, mouse; D016753:Interleukin-10