Control mechanisms for B cell apoptosis and differentiation

B 细胞凋亡和分化的控制机制

• 批准号: 06044130
• 负责人: TSUBATA Takeshi
• 金额: $ 9.34万
• 依托单位: Tokyo Medical and Dental University (1996)Kyoto University (1994-1995)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for international Scientific Research
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-06044130/
• 关键词: B lymphocyte; apoptosis; class switch; T lymphocyte; FDC; CD40; cell contact; 細胞接触; 濾泡性樹状細胞; CD40L; クラススッチ

We have assessed the regulatory mechanisms for B cell apoptosis and differentiation by T cells and follicular dendritic cells. For this purpose, we first established the cellular systems in which apoptosis of lined B cells is regulated by lined T cells or FDC,or defined molecules derived from these cells. Indeed, the B cell line WEHI-231 was rescued from antigen receptor-mediated apoptosis by either lined FDC or T cells expressing CD40L.Since FDC cells did not express ligands for CD40, FDC may rescue WEHI-231 cells by CD40-independent mechanisms. Moreover, CD40 signaling but not FDC induced expression of anti-apoptotic molecules, Bcl-2 and Bcl-x, suggesting that FDC rescues WEHI-231 cells by distinct mechanisms from CD40 signaling. In other studies, we found that the cyclin-dependent kinase inhibitor p27^<Kip1>, which negatively regulate cell cycle progression, is upregulated by antigen receptor signaling and down modulated by CD40 signaling in WEHI-231. When we cultured WEHI-231 in th … More e presence of the antisense oligonucleotides for p27^<Kip1>, WEHI-231 failed to undergo apoptosis upon antigen receptor crosslinking, suggesting that p27^<Kip1> is an important target molecule of CD40 signaling for B cell survival.We also established the cellular system in which molecular mechanisms for immunoglobulin class switching, a crucial step of B cell differentiation, can be assessed. We established a subclone (F3) of CH12 B lymphoma cells which undergo class switching frm IgM to IgA efficiently in the presence of CD40 ligand, IL-4 and TGF-beta. In these cells, Demethylation but not germline transcription of the C region of the immunoglobulin correlates to the efficiency of class switching. This result suggests that demethylation but not germ line transcription may play a role in class switching. To identify the molecules involved in class switching, we isolated two genes specifically expressed in F3 cells treated with CD40 ligand, IL-4 and TGF-beta. Functions of these genes are to be determined. Less

我们已经评估了T细胞和卵泡树突状细胞的B细胞凋亡和分化的调节机制。为此，我们首先建立了细胞系统，其中衬有衬里B细胞的细胞凋亡受衬里的T细胞或FDC调节，或从这些细胞中得出的定义分子。实际上，B细胞系WEHI-231从抗原受体介导的凋亡中通过衬里的FDC或表达CD40L的T细胞从抗原受体介导的凋亡中获取。由于FDC细胞并未表达CD40的配体，FDC可能会通过CD40独立机制营救WEHI-231细胞。此外，CD40信号传导而不是FDC诱导的抗凋亡分子Bcl-2和Bcl-X的表达，这表明FDC通过CD40信号传导的不同机制来拯救WEHI-231细胞。在其他研究中，我们发现细胞周期蛋白依赖性激酶抑制剂p27^<kip1>受负调节细胞周期进程的抗原受体信号传导和WEHI-231中CD40信号的调节。当我们在p27^<kip1>中培养WEHI-231时，在抗原受体交联时，更多的反义寡核苷酸的存在未能经历凋亡，这表明p27^<kip1>是CD40信号的重要范围，我们还不是在CD40信号的范围。免疫球蛋白的C区域的转录与类切换的效率相关。该结果表明，脱甲基化而不是种系转录可能在类切换中起作用。为了鉴定与类转换有关的分子，我们分离了两个在用CD40配体，IL-4和TGF-β处理的F3细胞中特异性表达的基因。这些基因的功能应确定。较少的

项目成果

Masao Murakami: "Prevention of autoimmune symptoms in autoimmune-prone mice by elimination of B-1 cells." International Immunology. 7. 877-882 (1995)

Masao Murakami：“通过消除 B-1 细胞来预防有自身免疫倾向的小鼠的自身免疫症状。”

Nakamura,M.: "High frequency class switching of an IgM^+ B lymphomaclons CH12F3 to IgA^+ cells." International Immunology. 8. 195-201 (1995)

Nakamura,M.：“IgM^ B 淋巴瘤克隆 CH12F3 到 IgA^ 细胞的高频类别转换。”

Murakami,M.,Tsubata T.,Shinkura,R.,Nisitani,S.,Okamoto,M.,Yoshioka,H.,Usui,T.,Miyawaki,S.Honjo,T.: "Oral administration of lipopolysaccharides activates B-1 cells in the peritoneal cavity and the lamina propria of the gut and induces autoimmune symptoms i

Murakami,M.,Tsubata T.,Shinkura,R.,Nisitani,S.,Okamoto,M.,Yoshioka,H.,Usui,T.,Miyawaki,S.Honjo,T.：“口服脂多糖可激活 B

Kohsaka H.: "The human immunoglobulin V(H) gene repertoire is genetically controlled and unaltered by chronic autoimmune stimulation." Journal of Clinical Investigation. 98. 2794-2800 (1996)

Kohsaka H.：“人类免疫球蛋白 V(H) 基因库受基因控制，不会因慢性自身免疫刺激而改变。”

Nomura,T.: "Antigen receptor-mediated B cell death is blocked by signaling via CD72 or treatment with dextran sulfate and is defective in autoimmunity-prone mice." Int.Immunol.8. 867-875 (1996)

Nomura,T.：“抗原受体介导的 B 细胞死亡被 CD72 信号传导或硫酸葡聚糖治疗所阻断，并且在易患自身免疫的小鼠中存在缺陷。”