Regulation of immunoglobulin gene expression in normal lymphocytes II. Mechanisms of down‐regulation of immunoglobulin secretion after engagement of the B cell antigen receptor

Berberich, Ingolf; Schimpl, Anneliese

doi:10.1002/eji.1830220235

Cited by 21 publications

(12 citation statements)

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“…This results in the downregulation of Mitf and Bach2, and subsequently, the release of Mitf-and Bach2-mediated repression of IRF4 [10] and 11,26], which finally drives terminal PC differentiation [18,27,28]. Our data and model also allow for full integration of other miRNAs, which are either down-or upregulated during a GC reaction, in the fine-tuning of GC reactions, and establishment of memory B and long-lived PCs.…”

Section: Discussionmentioning

confidence: 74%

miR‐148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2

et al. 2015

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B cells undergo affinity maturation and class switch recombination of their immunoglobulin receptors during a germinal center (GC) reaction, before they differentiate into longlived antibody-secreting plasma cells (PCs). Transcription factors such as Bach2 and Mitfare essential during this process, as they delay premature differentiation of GC B cells by repressing Blimp-1 and IRF4, two transcription factors required for terminal PC differentiation. Therefore, Bach2 and Mitf expression must be attenuated in activated B cells to allow terminal PC differentiation, but the precise mechanism remains enigmatic. Here, we provide evidence that miR-148a, a small noncoding microRNA, fosters PC differentiation and survival. Next-generation sequencing revealed that miR-148a is the most abundant microRNA in primary human and murine PCs, and its expression is upregulated in activated murine B cells and coincides with Blimp-1 synthesis. miR-148a targets Bach2, Mitf and proapoptotic factors such as PTEN and Bim. When prematurely expressed, miR-148a promotes the differentiation and survival of plasmablasts and reduces frequencies of IgG1 + cells in primary B-cell cultures. In summary, we propose that miR-148a is a new player in the regulatory network controlling terminal PC differentiation and could, therefore, be a therapeutic target for interfering with PC differentiation and survival.Keywords: B cells r Blimp-1 r MicroRNAs r miR-148a r Plasma cell differentiation r Bach2, Mitf See accompanying article by Haftmann et al.Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe generation of antibody-secreting plasma cells (PCs) and memory B cells is essential for eliminating pathogens and establishing Correspondence: Prof. Hans-Martin Jäck e-mail: hjaeck@molmed.uni-erlangen.de effective protection after vaccination. After antigen encounter, B cells are clonally expanded in the T-cell zone of a peripheral lymphatic organ and differentiate quickly into IgM-secreting short-lived PCs (extrafollicular pathway). If an antigen-activated * These authors contributed equally to this work.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1206-1215 Molecular immunology 1207B cell receives T-cell help, some of these cells move from the Tcell zone to a B-cell follicle located in the B-cell zone. There, they are further expanded, resulting in the formation of a germinal center (GC). During a GC reaction, B cells undergo somatic hypermutation (SHM) of their immunoglobulin variable region exons and class switch recombination (CSR). After B cells with highaffinity and class-switched antigen receptors have been selected, they leave the GC and differentiate either into memory B cells or long-lived PCs [1][2][3]. The differentiation of mature B cells into long-lived PCs via the GC pathway is tightly controlled by a regulatory network of mutually exclusive transcription factors; one set maintains the GC reaction, and the other is re...

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Section: Discussionmentioning

confidence: 74%

miR‐148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2

et al. 2015

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“…1 A, B). At the molecular level, IgM secretion was positively correlated with the expression of J chain- [20], and Blimp-1-specific mRNA (Fig. 1C): both mRNA were detectable in B cells stimulated with LPS only, whereas additional BCR ligation led to a loss of J chain expression and to a reduction in the level of Blimp-1 mRNA.…”

Section: Suppression Of Blimp-1 Expression and Up-regulation Of Iyl Smentioning

confidence: 84%

Blimp‐1 overcomes the block in IgM secretion in lipopolysaccharide / anti‐μ F(ab′)₂‐co‐stimulated B lymphocytes

Schliephake

Schimpl

1996

Eur J Immunol

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A combination of signals transmitted through the antigen receptor, membrane-bound cell interaction molecules and cytokine receptors induces B cell proliferation and differentiation into immunoglobulin-secreting or memory cells. It has recently been suggested by Turner et al. (Cell 1994. 77: 297) that the complex changes in gene activities accompanying high levels of immunoglobulin secretion are under the common control of a master regulator, Blimp-1 (B lymphocyte-induced maturation protein). We show here that in naive mouse B cells stimulated with lipopolysaccharide (LPS) alone (which leads to high IgM production), Blimp-1 is highly expressed, while cells co-stimulated with LPS and anti-mu F(ab')2 show low levels of Blimp-1 mRNA and no longer secrete Ig. I gamma 1 sterile transcripts are, however, up-regulated after receptor co-ligation. Addition of interleukin (IL)-2 and IL-5 to LPS + anti-mu F(ab')2-treated primary B cells led to up-regulation of Blimp-1 and IgM secretion. Transfection of a Blimp-1 expression vector also induced IgM secretion. The data indicate that Blimp-1 is an important regulator of immunoglobulin secretion by primary B cells, and suggest that its level of expression may determine the differentiation to Ig-secreting plasma cells or entrance and maintenance in the memory pool.

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“…were prepared as described (30,31) by a stepwise Percoll gradient (Amersham Biosciences). B cells were maintained in RPMI 1640 medium supplemented with 4.8 mM L-glutamine, 1 mM sodium pyruvate, 1ϫ nonessential amino acids (Invitrogen), 5% (v/v) fetal calf serum, streptomycin (0.2 mg/ml), penicillin (400 units/ml).…”

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The Stability and Anti-apoptotic Function of A1 Are Controlled by Its C Terminus

Herold

Zeitz

Pelzer

et al. 2006

Journal of Biological Chemistry

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Most Bcl-2 family members can localize to intracellular membranes via hydrophobic sequences within their C-terminal portion. We found that the C terminus of the anti-apoptotic family member A1 did not function as a membrane anchor. Instead, this stretch of the protein rendered A1 highly unstable by mediating its polyubiquitination and rapid proteasomal degradation. Moreover, the domain did not only function independently of its position within the A1 protein but when transfered could even destabilize unrelated proteins like enhanced green fluorescent protein and caspase-3. A1 was, however, much more stable in the presence of the Bcl-2 homology-only protein BimEL, suggesting that direct interaction of A1 with pro-apoptotic members of the Bcl-2 family strongly reduces its rate of turnover. We further show that the C-terminal end of A1 also contributes to the anti-apoptotic capacity of the protein. In conclusion, our data demonstrate that the C terminus serves a dual function by controlling the stability of A1 and by amplifying the capacity of the protein to protect cells against apoptosis.Apoptosis plays a critical role in tissue development and homeostasis. This is witnessed by the fact that a number of mammalian pathologies, including cancers and autoimmune and degenerative disorders, arise as a consequence of apoptotic processes going awry (1). Many apoptotic pathways converge at the mitochondria where they induce permeabilization of the outer mitochondrial membrane and subsequently the release of death-inducing factors such as cytochrome c (2, 3). The stability of the outer mitochondrial membrane is controlled by members of the Bcl-2 family (4), which are characterized by the presence of between one and four conserved regions termed Bcl-2 homology (BH) 4 domains (5). The Bcl-2 family consists of both pro-and anti-apoptotic members. The pro-apoptotic members can be further subdivided into those that possess multiple (two or three) BH domains, such as Bax and Bak, and those that possess only the short BH3 domain, such as Bim, Bad, Bid, and Noxa. The "BH3-only" proteins are thought to serve as sensors for different apoptotic stimuli and are stringently regulated at both the transcriptional and post-translational levels (6). The "multidomain" members, which are also referred to as "Bax/Bak-like" proteins, function downstream of their BH3-only relatives and are responsible for the formation of pores in the outer mitochondrial membrane (7). The antiapoptotic Bcl-2 proteins, of which Bcl-2 is the prototype, appear to protect the integrity of the outer mitochondrial membrane by sequestering and thereby neutralizing the pro-apoptotic family members (8 -10).Current models of apoptosis posit that the fate of a cell exposed to an apoptotic stimulus will depend on the balance between the pro-and anti-apoptotic Bcl-2 family members (11). One well recognized mechanism for regulating protein levels is via ubiquitin-mediated proteasomal degradation (12). Levels of Bim, for example, are normally kept low as a consequence of con...

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Regulation of immunoglobulin gene expression in normal lymphocytes II. Mechanisms of down‐regulation of immunoglobulin secretion after engagement of the B cell antigen receptor

Cited by 21 publications

References 17 publications

miR‐148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2

miR‐148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2

Blimp‐1 overcomes the block in IgM secretion in lipopolysaccharide / anti‐μ F(ab′)₂‐co‐stimulated B lymphocytes

The Stability and Anti-apoptotic Function of A1 Are Controlled by Its C Terminus

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Regulation of immunoglobulin gene expression in normal lymphocytes II. Mechanisms of down‐regulation of immunoglobulin secretion after engagement of the B cell antigen receptor

Cited by 21 publications

References 17 publications

miR‐148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2

miR‐148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2

Blimp‐1 overcomes the block in IgM secretion in lipopolysaccharide / anti‐μ F(ab′)2‐co‐stimulated B lymphocytes

The Stability and Anti-apoptotic Function of A1 Are Controlled by Its C Terminus

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Blimp‐1 overcomes the block in IgM secretion in lipopolysaccharide / anti‐μ F(ab′)₂‐co‐stimulated B lymphocytes