Repression of the Transcription Factor Bach2 Contributes to Predisposition of IgG1 Memory B Cells toward Plasma Cell Differentiation

Kometani, Kohei; Nakagawa, Rinako; Shinnakasu, Ryo; Kaji, Tomohiro; Rybouchkin, Andreï; Moriyama, Saya; Furukawa, Koji; Koseki, Haruhiko; Takemori, Toshitada; Kurosaki, Tomohiro

doi:10.1016/j.immuni.2013.06.011

Cited by 184 publications

(211 citation statements)

References 51 publications

(66 reference statements)

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“…The differential impacts on the TLR7 requirement for the memory stage versus the naive stage may represent either BCR-intrinsic or -extrinsic effects, or a combination of both; however, we believe that BCR-extrinsic effects are more significant for several reasons. (60). Moreover, several TLR genes themselves, including TLR7, were upregulated in memory B cells (61,62).…”

Section: Discussionmentioning

confidence: 96%

Whole-Virion Influenza Vaccine Recalls an Early Burst of High-Affinity Memory B Cell Response through TLR Signaling

Onodera

Hosono

Odagiri

et al. 2016

The Journal of Immunology

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Inactivated influenza vaccines have two formulations, whole- and split-virion types; however, how differential formulations impact their booster effects remain unknown. In this study, we demonstrate that whole-virion vaccines recall two waves of Ab responses, early T cell–independent (TI) and late T cell–dependent responses, whereas split-virion vaccines elicit the late T cell–dependent response only. Notably, higher-affinity Abs with improved neutralizing activity are provided from the early TI response, which emphasizes the important contribution of the formulation-dependent response in the protective immunity. Moreover, we show that the early TI response completely requires B cell–intrinsic TLR7 signaling, which can be delivered through viral RNAs within whole-virion vaccine. Thus, our results indicate that TLR agonists in whole-virion type improve recall Ab responses by directly targeting memory B cells, a finding with important implications for vaccine strategies aimed at the prompt recall of high-affinity neutralizing Abs.

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Section: Discussionmentioning

confidence: 96%

Whole-Virion Influenza Vaccine Recalls an Early Burst of High-Affinity Memory B Cell Response through TLR Signaling

Onodera

Hosono

Odagiri

et al. 2016

The Journal of Immunology

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“…Bach2 −/− mice have been previously described (6). FloxBach2 mice were generated by flanking ATG-containing exon 4 by two loxP sites (49). Neomycin resistant gene franked by FRT sequences was inserted into targeting vector for selecting ES cells.…”

Section: Methodsmentioning

confidence: 99%

Bach2 maintains T cells in a naive state by suppressing effector memory-related genes

Tsukumo

Unno

Muto

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The transcriptional repressor BTB and CNC homology 2 (Bach2) is thought to be mainly expressed in B cells with specific functions such as class switch recombination and somatic hypermutation, but its function in T cells is not known. We found equal Bach2 expression in T cells and analyzed its function using Bach2-deficient (−/−) mice. Although T-cell development was normal, numbers of peripheral naive T cells were decreased, which rapidly produced Th2 cytokines after TCR stimulation. Bach2 −/− naive T cells highly expressed genes related to effector-memory T cells such as CCR4, ST-2 and Blimp-1. Enhanced expression of these genes induced Bach2 −/− naive T cells to migrate toward CCR4-ligand and respond to IL33. Forced expression of Bach2 restored the expression of these genes. Using Chromatin Immunoprecipitation (ChIP)-seq analysis, we identified S100 calcium binding protein a, Heme oxigenase 1, and prolyl hydroxylase 3 as Bach2 direct target genes, which are highly expressed in effector-memory T cells. These findings indicate that Bach2 suppresses effector memory-related genes to maintain the naive T-cell state and regulates generation of effector-memory T cells. Kruppel-like factor 2 (KLF2) is one of those TF, which regulates the expression of the sphingosine-1-phosphate receptor-1 (S1pr1) in SP cells (2). S1pr1 is required for the egress of SP cells from the thymus, and thus KLF2-deficient (−/−) SP cells accumulate in the thymus. KLF2 positively regulates S1pr1 expression through direct binding to its promoter. KLF2 −/− mice also develop an unusual population of innate-like CD8 +

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“…Bach2 promotes CSR by delaying the expression of Blimp-1, the master regulator of plasma cell differentiation, and thereby securing a time window for CSR before the terminal differentiation to plasma cells (8 -10). A reduction in the Bach2 expression in memory B cells is involved in their rapid plasma cell differentiation upon antigen re-exposure (11). An integral view of the Bach2 functions in B cells has been proposed as a gene regulatory network (GRN) consisting of Bach2 and othertranscription factor genes (12).…”

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The Transcription Factor Bach2 Is Phosphorylated at Multiple Sites in Murine B Cells but a Single Site Prevents Its Nuclear Localization

Ando¹,

Shima

Tamahara

et al. 2016

Journal of Biological Chemistry

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2), and Irf (3) families have been well studied in the context of the immune system in part due to their clear and established association with the upstream signaling cascades. In contrast, although the phosphatidylinositol 3-kinase (PI3K) pathway is critically important for the regulation of immune cells, its downstream transcription factors are still unclear except for the Foxo family (4). In this study, we investigated the possibility that the transcription factor Bach2 might be regulated in B cells by the PI3K pathway. Salient features of Bach2 relevant to this study are as follows.Bach2 regulates the immune cells at multiple points. During the development of B cells from the progenitor cells, Bach2, together with its related factor Bach1, represses the expression of myeloid genes. The repression of the myeloid program is critical for the progenitor cells to be committed to the B cell fate (5). At the stage of pre-B cells, the successful completion of antibody heavy chain gene rearrangement is monitored by the lack or presence of pre-B cell receptor (pre-BCR 2 checkpoint). Bach2 plays a critical role in negative selection (i.e. elimination of cells unsuccessful in the rearrangement) at the pre-BCR checkpoint (6). In mature B cells, Bach2 is required for the class switch recombination (CSR) and somatic hypermutation that diversify the effector function and antigen affinity, respectively, of antibody molecules in response to antigen and other stimulation (7). Bach2 promotes CSR by delaying the expression of Blimp-1, the master regulator of plasma cell differentiation, and thereby securing a time window for CSR before the terminal differentiation to plasma cells (8 -10). A reduction in the Bach2 expression in memory B cells is involved in their rapid plasma cell differentiation upon antigen re-exposure (11). An integral view of the Bach2 functions in B cells has been proposed as a gene regulatory network (GRN) consisting of Bach2 and other * This work was supported by Grants-in-aid 15H02506, 25670156, 24390066, 23116003, 21249014, 17054028, and 25291042

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Repression of the Transcription Factor Bach2 Contributes to Predisposition of IgG1 Memory B Cells toward Plasma Cell Differentiation

Cited by 184 publications

References 51 publications

Whole-Virion Influenza Vaccine Recalls an Early Burst of High-Affinity Memory B Cell Response through TLR Signaling

Whole-Virion Influenza Vaccine Recalls an Early Burst of High-Affinity Memory B Cell Response through TLR Signaling

Bach2 maintains T cells in a naive state by suppressing effector memory-related genes

The Transcription Factor Bach2 Is Phosphorylated at Multiple Sites in Murine B Cells but a Single Site Prevents Its Nuclear Localization

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