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Ｂ細胞の選択と生存におけるオートファジーの役割

自噬在 B 细胞选择和存活中的作用

基本信息

批准号：
15F15908
负责人：
黒崎知博
金额：
$ 1.47万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for JSPS Fellows
财政年份：
2015
资助国家：
日本
起止时间：
2015-04-24 至 2017-03-31
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15F15908/
关键词：
Autophagy Germinal center Rubicon B cell survival Secretory autophagy B cell

项目摘要

Understanding the survival control mechanism of long-lived, antibody-producing cells and memory B cells at the germinal center (GC) is required for developing a effective vaccine against various infectious diseases including influenza viruses. It is unclear whether enhanced autophagy alters GC B cell differentiation. Rubicon, an autophagy suppressor, was up-regulated in activated B cells, suggesting that Rubicon may suppress autophagy in B cells. To address these questions, we generated pan-B cell- and GC-B cell-specific Rubicon-mutant mouse, respectively. A decrease in antigen-specific high-affinity antibody production and an increase in autoantibody such as anti-DNA antibody were found in Rubicon-mutant mice, suggesting that Rubicon may play a role in the selection of antigen-specific B cell. However, a small-molecular-weight protein that seems to be a Rubicon isoform was found in Rubicon-mutant B cells, suggesting that deletion of the Rubicon gene is incomplete. Thus, it is necessary to confirm the present results and clarify the function of each isoform of Rubicon with the complete Rubicon-deficient mouse. On the other hand, we unexpectedly found that CD40 signal specifically induced the secretion of LC3-II containing exosomes, suggesting that CD40 signal is involved in secretory autophagy. In addition, such secretion was enhanced in the Rubicon-mutant cells. CD40 is an essential molecule during B cell-T cell interaction, and further study of CD40-induced secretory autophagy may reveal a novel mechanism of lymphocyte interaction via secretory autophagy or exosome.

为了开发针对包括流感病毒在内的各种传染病的有效疫苗，需要了解在生殖中心（GC）的长寿命的抗体产生细胞和记忆B细胞的存活控制机制。尚不清楚增强的自噬是否改变GC B细胞分化。自噬抑制因子Rubicon在活化的B细胞中表达上调，提示Rubicon可能抑制B细胞的自噬。为了解决这些问题，我们分别产生了泛B细胞和GC-B细胞特异性Rubicon突变小鼠。Rubicon基因突变小鼠产生的抗原特异性高亲和力抗体减少，抗DNA抗体等自身抗体增加，提示Rubicon基因可能在抗原特异性B细胞的选择中起作用。然而，在Rubicon突变型B细胞中发现了一种似乎是Rubicon同种型的小分子量蛋白，这表明Rubicon基因的缺失是不完全的。因此，有必要用完整的Rubicon缺陷小鼠来证实本结果并阐明Rubicon的每种异构体的功能。另一方面，我们意外地发现，CD 40信号特异性地诱导含有LC 3-II的外泌体的分泌，这表明CD 40信号参与分泌性自噬。此外，这种分泌在Rubicon突变细胞中增强。CD 40是B细胞与T细胞相互作用的重要分子，对CD 40诱导的分泌性自噬的进一步研究可能揭示分泌性自噬或外泌体介导的淋巴细胞相互作用的新机制。