Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Autophagy. 2013 Apr;9(4):528-37. doi: 10.4161/auto.23484. Epub 2013 Jan 17.
Autophagy is a conserved homeostatic process in which cytoplasmic contents are degraded and recycled. Two ubiquitin-like conjugation pathways are required for the generation of autophagosomes, and ATG5 is necessary for both of these processes. Studies of mice deficient in ATG5 reveal a key role for autophagy in T lymphocyte function, as well as in B cell development and B-1a B cell maintenance. However, the role of autophagy genes in B cell function and antibody production has not been described. Using mice in which Atg5 is conditionally deleted in B lymphocytes, we showed here that this autophagy gene is essential for plasma cell homeostasis. In the absence of B cell ATG5 expression, antibody responses were significantly diminished during antigen-specific immunization, parasitic infection and mucosal inflammation. Atg5-deficient B cells maintained the ability to produce immunoglobulin and undergo class-switch recombination, yet had impaired SDC1 expression, significantly decreased antibody secretion in response to toll-like receptor ligands, and an inability to upregulate plasma cell transcription factors. These results build upon previous data demonstrating a role for ATG5 in early B cell development, illustrating its importance in late B cell activation and subsequent plasma cell differentiation.
自噬是一种保守的稳态过程，其中细胞质内容物被降解和回收。生成自噬体需要两种泛素样连接途径，而 ATG5 对于这两种途径都是必需的。研究缺乏 ATG5 的小鼠揭示了自噬在 T 淋巴细胞功能以及 B 细胞发育和 B-1a B 细胞维持中的关键作用。然而，自噬基因在 B 细胞功能和抗体产生中的作用尚未描述。在这里，我们使用条件性缺失 B 淋巴细胞中 Atg5 的小鼠表明，该自噬基因对于浆细胞稳态是必需的。在缺乏 B 细胞 ATG5 表达的情况下，抗原特异性免疫接种、寄生虫感染和黏膜炎症期间抗体反应显著减弱。缺乏 Atg5 的 B 细胞保持产生免疫球蛋白和发生类别转换重组的能力，但其 SDC1 表达受损，对 Toll 样受体配体的抗体分泌显著减少，并且无法上调浆细胞转录因子。这些结果建立在先前的数据基础上，表明 ATG5 在早期 B 细胞发育中起作用，说明其在晚期 B 细胞激活和随后的浆细胞分化中的重要性。
