Novel Role of the Ras Cascade in Memory B Cell Response

Takahashi, Yoshimasa; Inamine, Ayako; Hashimoto, Shu-ichi; Haraguchi, Sachiko; Yoshioka, Emi; Kojima, Naoya; Ryo, Akihide; Takemori, Toshitada

doi:10.1016/j.immuni.2005.06.010

Cited by 29 publications

(28 citation statements)

References 47 publications

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“…The results of this analysis indicate that Spry2 expression is induced within approximately 10 to 12 hours of BCR engagement, a response that is dependent on MAPK-ERK activation ( Figure 5). MAPK-ERK pathway signaling initiates events that lead to B-cell proliferation 57,58 and differentiation. 59 Our data further suggest that SPRY2 protein expression subsequently represses MAPK-ERK signaling, thus establishing a SPRY2-mediated autoregulatory loop that dampens the antigen-induced expansion of mature B cells (see model, Figure 7F, WT).…”

Section: Discussionmentioning

confidence: 99%

Expression of sprouty2 inhibits B-cell proliferation and is epigenetically silenced in mouse and human B-cell lymphomas

Frank¹,

Dawson²,

Bensinger

et al. 2009

Blood

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B-cell lymphoma is the most common immune system malignancy. TCL1 transgenic mice (TCL1-tg), in which TCL1 is ectopically expressed in mature lymphocytes, develop multiple B-and T-cell leukemia and lymphoma subtypes, supporting an oncogenic role for TCL1 that probably involves AKT and MAPK-ERK signaling pathway augmentation. Additional, largely unknown genetic and epigenetic alterations cooperate with TCL1 during lymphoma progression. We examined DNA methylation patterns in TCL1-tg Bcell tumors to discover tumor-associated IntroductionHyperactivation of the RAS-RAF-MEK-ERK signaling pathway (MAPK-ERK pathway) promotes a variety of cancers, including hematologic malignancies, by enhancing cell proliferation and cell survival and by affecting differentiation. 1,2 The MAPK-ERK pathway can be constitutively activated by tumor type-specific gain-of-function mutations in (or overexpression of) upstream pathway members, such as growth factor receptors, RAS, and RAF, and by loss-of-function mutations in (or repression of) negative pathway regulators, such as NF1, SPROUTY, or SPRED proteins. 3 Ectopic expression of T-cell leukemia 1 (TCL1), a gene that encodes a 14-kDa protein that augments AKT pathway signaling in lymphocytes, is common in mature B-cell leukemias and lymphomas. [4][5][6] A causative role for ectopic TCL1 expression in lymphocyte transformation is supported by the observation that a spectrum of Tand B-cell tumors form in TCL1 transgenic (TCL1-tg) mice, in which the human TCL1 gene is ectopically expressed under the control of an E-B29 promoter in mature lymphocytes. 7 The mechanism(s) by which ectopic TCL1 expression promotes T and B lymphocyte transformation is not fully understood. In T cells, TCL1 augments AKT and MAPK-ERK signaling with each pathway independently contributing to increase T-cell proliferation in TCL1-tg mice. 8 There is also evidence that the tumorigenic activity of TCL1 involves more than augmentation of AKT signaling because it has been shown that increasing AKT activity in B cells to levels higher than are detected in TCL1-tg B cells by deleting Pten, a negative regulator of AKT, fails to cause lymphocyte transformation. 9 Moreover, it is not known what effect TCL1 has on MAPK-ERK signaling in B cells. The observation that in humans and TCL1-tg mice there is a long latency before B-and T-cell tumors form after ectopic expression of TCL1 is consistent with the conclusion that additional changes beyond TCL1-mediated augmentation of AKT signaling are needed to transform lymphocytes.Because TCL1 expression is more frequently dysregulated in B-cell compared with T-cell tumors, we have focused on its role in B-cell malignancies. B-cell lymphomas from TCL1-tg mice display aneuploidy and chromosomal translocations. In many of these lymphomas, trisomy 15 and its associated c-MYC overexpression results in a lesion that histologically and molecularly resembles human Burkitt lymphoma (BL). 10,11 In addition to genetic alterations, TCL1-tg B-cell tumors also display reproducible genomewide p...

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Section: Discussionmentioning

confidence: 99%

Expression of sprouty2 inhibits B-cell proliferation and is epigenetically silenced in mouse and human B-cell lymphomas

Frank¹,

Dawson²,

Bensinger

et al. 2009

Blood

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“…Functionally, B mem cells can be defi ned as long-lived Ag-experienced B cells that rapidly produce Ab in response to re-challenge with soluble, adjuvant-free Ags aft er being transferred into recipient mice together with cognate Th cells 30 . Th is assay should be potentially useful to identify factors that aff ect development, longevity, in situ localization, Ag responsiveness and so on of B mem cells, but their paucity and in vitro fragility have limited these applications, except for using specifi c mutant mouse strains 27,31,32 .…”

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confidence: 99%

In-vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivo

et al. 2011

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In response to T cell-dependent antigens, B cells proliferate extensively to form germinal centres (GC), and then differentiate into memory B (B mem ) cells or long-lived plasma cells (LLPCs) by largely unknown mechanisms. Here we show a new culture system in which mouse na ï ve B cells undergo massive expansion and isotype switching, and generate GC-phenotype B (iGB) cells. The iGB cells expressing IgG1 or IgM / D, but not IgE, differentiate into B mem cells in vivo after adoptive transfer and can elicit rapid immune responses with the help of cognate T cells. Secondary culture with IL-21 maintains the proliferation of the iGB cells, while shifting their in vivo developmental fate from B mem cells to LLPCs, an outcome that can be reversed by withdrawal of IL-21 in tertiary cultures. Thus, this system enables in vitro manipulation of B-cell fate, into either B mem cells or LLPCs, and will facilitate dissection of GC-B cell differentiation programs.

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“…21) In transgenic mice expressing the dominant-negative form of Ha-ras, the memory B cell response was significantly impaired while the primary B cell response to T-dependent antigen was normal. Furthermore, purified memory B cells deficient in Ras signaling did not differentiate into plasma cells in response to antigenic stimulation, but instead died by apoptosis.…”

Section: )mentioning

confidence: 99%

Memory B Cells in Systemic and Mucosal Immune Response: Implications for Successful Vaccination

Takahashi

2007

Bioscience, Biotechnology, and Biochemistry

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B-cell memory has been extensively analyzed in the systemic immune response elicited by hapten-carrier antigens, and the regulatory mechanisms underlying the process are beginning to be elucidated. Memory B cells can be generated through heterogeneous pathways within and outside germinal centers (GCs). Once developed, they appear to be maintained like stem cells for long periods by homeostatic proliferation. In response to reencountered antigens, memory B cells robustly secrete antibodies with help of the anti-apoptotic effect of Rasmediated signals. We have recently found that following intranasal infection with an influenza virus, virusspecific memory B cells develop in the lungs and persist for a long time along with GC B cells and plasma cells; this appears to be unique feature of the mucosal memory response. Thus memory B cell responses in the systemic and mucosal sites are regulated by distinct processes and further understanding of them should provide a theoretical framework for the development of new vaccine strategies.

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Novel Role of the Ras Cascade in Memory B Cell Response

Cited by 29 publications

References 47 publications

Expression of sprouty2 inhibits B-cell proliferation and is epigenetically silenced in mouse and human B-cell lymphomas

Expression of sprouty2 inhibits B-cell proliferation and is epigenetically silenced in mouse and human B-cell lymphomas

In-vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivo

Memory B Cells in Systemic and Mucosal Immune Response: Implications for Successful Vaccination

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