Ｂ細胞の選択と生存におけるオートファジーの役割

了解生发中心（GC）的长寿命、产生抗体的细胞和记忆B细胞的生存控制机制，是开发针对包括流感病毒在内的各种传染病的有效疫苗的必要条件。目前尚不清楚增强的自噬是否会改变GC B细胞的分化。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，我们分别生成了pan-B细胞和GC-B细胞特异性rubicon突变小鼠。Rubicon突变小鼠的抗原特异性高亲和力抗体产生减少，自身抗体如抗dna抗体增加，提示Rubicon可能在抗原特异性B细胞的选择中起作用。然而，在Rubicon突变的B细胞中发现了一种小分子量的蛋白，似乎是Rubicon的异构体，这表明Rubicon基因的缺失是不完整的。因此，有必要在完全Rubicon缺失小鼠中证实目前的结果并阐明Rubicon各亚型的功能。另一方面，我们意外发现CD40信号特异性诱导含有LC3-II的外泌体分泌，提示CD40信号参与了分泌性自噬。此外，这种分泌在rubicon突变细胞中增强。CD40是B细胞- t细胞相互作用中必不可少的分子，进一步研究CD40诱导的分泌性自噬可能揭示淋巴细胞通过分泌性自噬或外泌体相互作用的新机制。

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.