title: Control of Toll-like receptor-mediated T cell-independent type 1 antibody responses by the inducible nuclear protein IκB-ζ.
abstract: Antibody responses have been classified as being either T cell-dependent or T cell-independent (TI). TI antibody responses are further classified as being either type 1 (TI-1) or type 2 (TI-2), depending on their requirement for B cell-mediated antigen receptor signaling. Although the mechanistic basis of antibody responses has been studied extensively, it remains unclear whether different antibody responses share similarities in their transcriptional regulation. Here, we show that mice deficient in IκB-ζ, specifically in their B cells, have impaired TI-1 antibody responses but normal T cell-dependent and TI-2 antibody responses. The absence of IκB-ζ in B cells also impaired proliferation triggered by Toll-like receptor (TLR) activation, plasma cell differentiation, and class switch recombination (CSR). Mechanistically, IκB-ζ-deficient B cells could not induce TLR-mediated induction of activation-induced cytidine deaminase (AID), a class-switch DNA recombinase. Retroviral transduction of AID in IκB-ζ-deficient B cells restored CSR activity. Furthermore, acetylation of histone H3 in the vicinity of the transcription start site of the gene that encodes AID was reduced in IκB-ζ-deficient B cells relative to IκB-ζ-expressing B cells. These results indicate that IκB-ζ regulates TLR-mediated CSR by inducing AID. Moreover, IκB-ζ defines differences in the transcriptional regulation of different antibody responses.
authors.affiliation: From the Laboratory of Cell Recognition and Response, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8578.
authors.forename: Fumito
authors.initials: F
authors.lastname: Hanihara-Tatsuzawa
authors.affiliation: From the Laboratory of Cell Recognition and Response, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8578.
authors.forename: Hanae
authors.initials: H
authors.lastname: Miura
authors.affiliation: From the Laboratory of Cell Recognition and Response, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8578.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: the Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Isagawa
authors.affiliation: From the Laboratory of Cell Recognition and Response, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8578.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Okuma
authors.affiliation: the Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, and.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Manabe
authors.affiliation: From the Laboratory of Cell Recognition and Response, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8578, the Laboratory of Cell Signaling, School of Medicine, Gifu University, Gifu 501-1194, Japan ta-maru@umin.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: MaruYama
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000483:Alleles; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D001402:B-Lymphocytes / Q000378:metabolism*; D019013:CD40 Antigens / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D003564:Cytidine Deaminase / Q000378:metabolism; D005786:Gene Expression Regulation; D006657:Histones / Q000737:chemistry; D017578:Immunoglobulin Class Switching; D008070:Lipopolysaccharides / Q000737:chemistry; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D045522:Recombinases / Q000378:metabolism; D011995:Recombination, Genetic; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019013:CD40 Antigens; D006657:Histones; D008070:Lipopolysaccharides; C485947:Nfkbiz protein, mouse; D009687:Nuclear Proteins; D011947:Receptors, Antigen, B-Cell; D045522:Recombinases; D051193:Toll-Like Receptors; D003564:Cytidine Deaminase
keywords: Activation-induced Cytidine Deaminase (AID); B Cell; Cell Differentiation; Cellular Immune Response; Immunology; IκB-z; Toll-like Receptor (TLR); Transcription Factor