title: Type I IFN Contributes to the Phenotype of Unc93b1D34A/D34A Mice by Regulating TLR7 Expression in B Cells and Dendritic Cells.
abstract: TLR7 recognizes pathogen-derived and self-derived RNA, and thus a regulatory system for control of the TLR7 response is required to avoid excessive activation. Unc93 homolog B1 (Unc93B1) is a regulator of TLR7 that controls the TLR7 response by transporting TLR7 from the endoplasmic reticulum to endolysosomes. We have previously shown that a D34A mutation in Unc93B1 induces hyperactivation of TLR7, and that Unc93b1(D34A/D34A) mice (D34A mice) have systemic inflammation spontaneously. In this study, we examined the roles of inflammatory cytokines such as IFN-γ, IL-17A, and type I IFNs to understand the mechanism underlying the phenotype in D34A mice. mRNAs for IFN-γ and IL-I7A in CD4(+) T cells increased, but inflammatory phenotype manifesting as thrombocytopenia and splenomegaly was still observed in Ifng(-/-) or Il17a(-/-) D34A mice. In contrast to T cell-derived cytokines, Ifnar1(-/-) D34A mice showed an ameliorated phenotype with lower expression of TLR7 in B cells and conventional dendritic cells (cDCs). The amount of TLR7 decreased in B cells from Ifnar1(-/-) D34A mice, but the percentage of TLR7(+) cells decreased among CD8α(-) cDCs. In conclusion, type I IFNs maintain expression of TLR7 in B cells and cDCs in different ways; total amount of TLR7 is kept in B cells and TLR7(+) population is retained among cDCs. Our results suggested that these TLR7-expressing cells are activated initially and influence TLR7-dependent systemic inflammation.
authors.affiliation: Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; and.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Fukui
authors.affiliation: Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; and Laboratory of Innate Immunity, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Kanno
authors.affiliation: Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; and Laboratory of Innate Immunity, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan kmiyake@ims.u-tokyo.ac.jp.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Miyake
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016827:CD8 Antigens / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007370:Interferon Type I / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D026901:Membrane Transport Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D013163:Splenomegaly / Q000276:immunology; D013921:Thrombocytopenia / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000096:biosynthesis*
chemical_list: D016827:CD8 Antigens; C508032:Ifnar1 protein, mouse; C098680:Il17a protein, mouse; D007370:Interferon Type I; D020381:Interleukin-17; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; C512254:UNC93B1 protein, mouse; D053633:Receptor, Interferon alpha-beta; D007371:Interferon-gamma