Canonical autophagy dependent on the class III phosphoinositide-3 kinase Vps34 is required for naive T-cell homeostasis
Canonical autophagy dependent on the class III phosphoinositide-3 kinase Vps34 is required for naive T-cell homeostasis
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DOI：
10.1073/pnas.1205305109
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发表时间：
2012-05-29
影响因子：
11.1
通讯作者：
Flavell, Richard A.
中科院分区：
文献类型：
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作者：
Willinger, Tim;Flavell, Richard A.
幼稚T细胞的稳态对于针对感染的保护性免疫是必不可少的，但是控制幼稚T细胞稳态的细胞内在分子机制知之甚少。在低等生物体中的基因消融已经揭示了Vps 34（一种进化上保守的III类磷酸肌醇-3激酶（PI 3 K））在调节内吞作用和自噬中的关键作用;然而，Vps 34在免疫系统（特别是在T细胞中）中的生理功能尚不清楚。在这里，我们报告说，Vps 34是维持幼稚T细胞所必需的，以细胞内在的方式发挥作用。编码Vps 34的基因的T细胞特异性缺失导致Vps 15和Beclin-1（III类PI 3 K复合物的组分）的稳定性降低，并损害T细胞中的自噬。Vps 34对T细胞发育是不利的，但对幼稚T细胞的存活是重要的。Vps 34缺陷型T细胞显示线粒体质量增加和活性氧物质积累，与受损线粒体的去除不足一致。因此，Vps 34依赖性典型自噬通过线粒体的质量控制促进T细胞存活，在维持T细胞稳态中起关键作用。
The homeostasis of naive T cells is essential for protective immunity against infection, but the cell-intrinsic molecular mechanisms that control naive T-cell homeostasis are poorly understood. Genetic ablation in lower organisms has revealed a critical role for Vps34, an evolutionary conserved class III phosphoinositide-3 kinase (PI3K), in regulating endocytosis and autophagy; however, the physiological function of Vps34 in the immune system, especially in T cells, is unclear. Here we report that Vps34 is required for the maintenance of naive T cells, acting in a cell-intrinsic manner. T-cell-specific deletion of the gene encoding Vps34 resulted in reduced stability of Vps15 and Beclin-1, components of the class III PI3K complex, and impaired autophagy in T cells. Vps34 was dispensable for T-cell development but important for the survival of naive T cells. Vps34-deficient T cells showed increased mitochondrial mass and accumulation of reactive oxygen species, consistent with deficient removal of damaged mitochondria. Thus, Vps34-dependent canonical autophagy plays a critical role in maintaining T-cell homeostasis by promoting T-cell survival through quality control of mitochondria.