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)中长寿命的抗体产生细胞和记忆B细胞的生存控制机制，是开发有效的针对包括流感病毒在内的各种传染病的疫苗的必要条件。目前尚不清楚增强的自噬是否会改变GC B细胞的分化。在激活的B细胞中，自噬抑制因子Rubcon被上调，这表明它可能抑制B细胞的自噬。为了解决这些问题，我们分别培育了PAN-B细胞和GC-B细胞特异的Rubcon突变小鼠。在Rubcon基因突变的小鼠中，发现抗原特异性高亲和力抗体的产生减少，抗DNA抗体等自身抗体的产生增加，提示Rubcon基因可能在抗原特异性B细胞的选择中发挥作用。然而，在Rubcon突变的B细胞中发现了一种小分子蛋白质，似乎是Rubcon异构体，这表明Rubcon基因的缺失是不完整的。因此，有必要证实目前的结果，并阐明每一种异构体的功能与完全缺乏Rubcon的小鼠的功能。另一方面，我们意外地发现CD40信号特异性地诱导含有外切体的LC3-II的分泌，提示CD40信号参与了分泌型自噬。此外，在Rubcon突变细胞中，这种分泌也得到了增强。CD40是B细胞-T细胞相互作用的重要分子，对CD40诱导的分泌性自噬的进一步研究可能揭示一种新的机制，即通过分泌性自噬或外体与淋巴细胞相互作用。

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.