Switch recombination and germ-line transcription are division-regulated events in B lymphocytes

McCall, Martin N.; Hodgkin, Philip D.

doi:10.1016/s0167-4781(99)00131-1

Cited by 24 publications

(22 citation statements)

References 29 publications

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“…We were particularly interested in investigating the division-linked regulation of S region targeting because previous results had indicated that expression of ␥1 transcripts increased with successive cell divisions (27). This result suggested that the induction of S-region accessibility might regulate division-linked CSR.…”

Section: Discussionmentioning

confidence: 99%

Expression of activation-induced cytidine deaminase is regulated by cell division, providing a mechanistic basis for division-linked class switch recombination

Rush

Liu

Odegard

et al. 2005

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

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Class switch recombination (CSR) is the process by which B cells alter the effector function properties of their Ig molecules. The decision to switch to a particular Ig isotype is determined primarily by the mode of B cell activation and cytokine exposure. More recent work indicates that the likelihood or probability of switching increases with successive cell divisions and is largely independent of time. We have analyzed different molecular features of CSR using cell division as a reference point in an attempt to gain insight into the mechanism of division-linked switching. Our results indicated that the accessibility of Ig heavy chain constant regions targeted for CSR was established after the cells had undergone a single cell division and did not vary significantly with subsequent cell divisions. In contrast, expression of activation-induced cytidine deaminase (AID) mRNA was found to increase with successive divisions, exhibiting a striking correlation with the frequency of CSR. Levels of AID in a given division remained constant at different time points, strongly suggesting that the regulation of AID expression was division-linked and independent of time. In addition, constitutive AID expression from a transgene accelerated division-linked CSR. Thus, we propose that the division-linked increase in AID expression provides an underlying molecular explanation for division-linked CSR.B lymphocyte ͉ cell division C lass switch recombination (CSR) is a region-specific DNA recombination mechanism that occurs by exchanging the currently expressed Ig heavy chain constant region (C H ) for another downstream C H region. CSR enables B cells to alter the effector properties of their Ig molecules without altering their antigen specificity. Conceptually, class switching can be divided into three stages of targeting, cleavage, and DNA repair͞rejoining, with specific molecular events associated with each stage. For example, cytokine-induced C H region accessibility is marked by acetylation of histone proteins and germ-line transcription across targeted switch (S) regions (1, 2), highly repetitive sequences upstream of each C H gene except C␦. S region cleavage involves the introduction of DNA lesions in S regions targeted for recombination (3-5), and finally, the rejoining of the cleaved ends requires a number of ubiquitously expressed DNA repair factors. In addition, CSR absolutely requires the activity of the activation-induced cytidine deaminase (AID) (6). Although originally speculated to be an RNA-editing enzyme, recent data strongly suggest that AID functions as a DNA deaminase (7,8), acting in the context of transcription to deaminate cytosines on single-stranded DNA templates within S regions before the introduction of double-stranded lesions (9-11).Class switching to particular Ig isotypes in vivo is determined by a combination of exposure to pathogenic stimuli, T cell help, and particular cytokines (reviewed in ref. 12). Induction of switching to all of the different Ig isotypes can be recapitulated ex vivo, which...

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Section: Discussionmentioning

confidence: 99%

Expression of activation-induced cytidine deaminase is regulated by cell division, providing a mechanistic basis for division-linked class switch recombination

Rush

Liu

Odegard

et al. 2005

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

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“…It is known that both the processes of CSR and PC differentiation are intimately linked to proliferation (12,21). Therefore, we sought to determine the impact of a B-cell-intrinsic GC defect on humoral immunity.…”

Section: Wt and Ccnd3mentioning

confidence: 99%

Cyclin D3 Is Selectively Required for Proliferative Expansion of Germinal Center B Cells

Cato

Chintalapati

Yau

et al. 2011

Molecular and Cellular Biology

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The generation of robust T-cell-dependent humoral immune responses requires the formation and expansion of germinal center structures within the follicular regions of the secondary lymphoid tissues. B-cell proliferation in the germinal center drives ongoing antigen-dependent selection and the generation of highaffinity class-switched plasma and memory B cells. However, the mechanisms regulating B-cell proliferation within this microenvironment are largely unknown. Here, we report that cyclin D3 is uniquely required for germinal center progression. Ccnd3 ؊/؊ mice exhibit a B-cell-intrinsic defect in germinal center maturation and fail to generate an affinity-matured IgG response. We determined that the defect resulted from failed proliferative expansion of GL7 ؉ IgD ؊ PNA ؉ B cells. Mechanistically, sustained expression of cyclin D3 was found to be regulated at the level of protein stability and controlled by glycogen synthase kinase 3 in a cyclic AMP-protein kinase A-dependent manner. The specific defect in proliferative expansion of GL7 ؉ IgD ؊ PNA ؉ B cells in Ccnd3 ؊/؊ mice defines an underappreciated step in germinal center progression and solidifies a role for cyclin D3 in the immune response, and as a potential therapeutic target for germinal center-derived B-cell malignancies.The T-cell-dependent (TD) adaptive immune response is typified by the generation of high-affinity antigen (Ag)-specific memory B cells and antibody-secreting plasma cells (PCs) that have undergone class switch recombination (CSR) to IgG or IgE isotypes. The generation of these cells has long been known to occur in secondary lymphoid tissues within the unique microenvironment of the germinal center (GC). After Ag binding and activation via the B-cell receptor complex (BCR), B cells migrate to the T-cell zone, where additional costimulation is provided by cognate helper T cells. A cohort of these activated B cells go on to colonize GCs, which upon maturation represent an oligoclonal expansion of Ag-specific B cells (14,18).Within the GC, B cells undergo rapid proliferative expansion in response to Ag bound by follicular dendritic cells (FDCs). In humans, histological examination of the GC reveals distinct dark and light zones defined by the presence of proliferating centroblasts and largely nonproliferating centrocytes, respectively. Evidence suggests that centroblasts represent early GC cells that undergo somatic hypermutation (SHM), CSR and proliferative expansion, while centrocytes undergo affinity-based selection and differentiation events, leading to commitment to the memory or PC sublineages and exit from the GC. Although the organization of the GC is less distinct in mice, recent work has shown that chemokine-directed migration, FDC interaction, and proliferation may distinguish early and late GC B cells (1). Despite significant advances in understanding GC B-cell differentiation using multiparameter flow cytometry and intravital imaging, the initial colonization of GC "founder" B cells and their subsequent proliferative expansi...

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“…17,18 Briefly, purified splenic B cells from Stat6 Ϫ/Ϫ mice or littermate WT mice were incubated with 5-(and-6)-carboxyfluorescein diacetate, succinimidyl ester (CFSE, 10 M; Molecular Probes, Eugene, OR) in PBS at 37°C for 10 minutes and then washed with RPMI 1640 medium. CFSE-labeled B cells were cultured at 37°C for 6 days with LPS (10 g/mL) in the presence of IL-4 (50 ng/mL) and indicated amounts of IL-21 (0-20 ng/mL).…”

Section: Membrane Ige ؉ B Cells With Cell Divisionmentioning

confidence: 99%

Interleukin 21 prevents antigen-induced IgE production by inhibiting germ line Cε transcription of IL-4–stimulated B cells

Suto

Nakajima

Hirose

et al. 2002

Blood

209

188

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Interleukin 21 (IL-21) has recently been identified as a multifunctional cytokine that induces the proliferation of T cells and B cells and differentiation of natural killer cells. To determine whether IL-21 regulates IL-4–mediated immune responses, we examined the effect of IL-21 on antigen-specific IgE production in mice. We also examined the effect of IL-21 on IL-4–induced IgE production from B cells and antigen-induced T-helper 2 (Th2) cell differentiation. The in vivo injection of IL-21 prevented antigen-specific IgE but not IgG2a production on immunization. IL-21 did not affect Th2 cell differentiation or IL-4 production from CD4+ T cells but directly inhibited IL-4–induced IgE production from B cells at single-cell levels. Moreover, IL-21 inhibited IL-4–induced germ line Cε transcription in B cells without the inhibition of signal transducer and activator of transcription 6 (Stat6) activation. Taken together, these results indicate that IL-21 down-regulates IgE production from IL-4–stimulated B cells through the inhibition of germ line Cε transcription and thus suggest that IL-21 may be useful for the treatment of IgE-dependent allergic diseases.

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Switch recombination and germ-line transcription are division-regulated events in B lymphocytes

Cited by 24 publications

References 29 publications

Expression of activation-induced cytidine deaminase is regulated by cell division, providing a mechanistic basis for division-linked class switch recombination

Expression of activation-induced cytidine deaminase is regulated by cell division, providing a mechanistic basis for division-linked class switch recombination

Cyclin D3 Is Selectively Required for Proliferative Expansion of Germinal Center B Cells

Interleukin 21 prevents antigen-induced IgE production by inhibiting germ line Cε transcription of IL-4–stimulated B cells

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