A role for autophagic protein beclin 1 early in lymphocyte development.
A role for autophagic protein beclin 1 early in lymphocyte development.
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DOI：
10.4049/jimmunol.1002223
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发表时间：
2011-02-15
期刊：
影响因子：
--
通讯作者：
Ortiz BD
中科院分区：
文献类型：
--
作者：
Arsov I;Adebayo A;Kucerova-Levisohn M;Haye J;MacNeil M;Papavasiliou FN;Yue Z;Ortiz BD
自噬是一种高度调节和进化保守的细胞自我消化过程。最近的证据表明，这一过程在调节T细胞稳态中起着重要作用。在这项研究中，我们利用Rag 1 −/−囊胚互补和体外胚胎干细胞（ES）分化来解决Beclin 1（关键自噬蛋白之一）在淋巴细胞发育中的作用。与对照小鼠相比，Beclin 1缺陷型Rag 1−/−嵌合体显示胸腺细胞结构显著减少。利用ESC的体外分化，我们发现不能维持正常的胸腺细胞结构可能是由胸腺祖细胞的维持受损引起的。有趣的是，尽管胸腺细胞数量急剧减少，但Beclin 1缺陷型Rag 1−/−嵌合体的外周T细胞区室基本正常。尽管自噬体的数量显著减少，但外周T细胞显示正常的体外增殖。此外，与对照组相比，这些嵌合体的骨髓中早期B细胞的数量大大减少。然而，外周B细胞区室没有受到Beclin 1缺陷的显著影响。总的来说，我们的研究结果表明，Beclin 1是维持未分化/早期淋巴细胞祖细胞群所必需的。相比之下，Beclin 1在很大程度上与外周T和B细胞区室的初始生成和功能有关。这表明正常的淋巴细胞发育涉及Beclin 1依赖性的早期阶段和不同的Beclin 1不依赖性的晚期阶段过程。
Autophagy is a highly regulated and evolutionarily conserved process of cellular self-digestion. Recent evidence suggests that this process plays an important role in regulating T cell homeostasis. In this study, we have utilized Rag1−/− blastocyst complementation and in vitro embryonic stem (ES) cell differentiation to address the role of Beclin 1, one of the key autophagic proteins, in lymphocyte development. Beclin 1-deficient Rag 1−/− chimeras displayed a dramatic reduction in thymic cellularity compared to control mice. Using ESC differentiation in vitro, we found that the inability to maintain normal thymic cellularity is likely caused by impaired maintenance of thymocyte progenitors. Interestingly, despite drastically reduced thymocyte numbers, the peripheral T cell compartment of Beclin 1-deficient Rag 1−/− chimeras is largely normal. Peripheral T cells displayed normal in vitro proliferation despite significantly reduced numbers of autophagosomes. In addition, these chimeras had greatly reduced numbers of early B cells in the bone marrow compared to controls. However, the peripheral B cell compartment was not dramatically impacted by Beclin 1 deficiency. Collectively, our results suggest that Beclin 1 is required for maintenance of undifferentiated/early lymphocyte progenitor populations. In contrast, Beclin 1 is largely dispensable for the initial generation and function of the peripheral T and B cell compartments. This indicates that normal lymphocyte development involves Beclin 1-dependent early-stage, and distinct, Beclin 1-independent, late stage processes.
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发表时间：
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期刊：
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影响因子：
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