Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Cell Death Differ. 2012 Jan;19(1):144-52. doi: 10.1038/cdd.2011.78. Epub 2011 Jun 10.
Autophagy is implicated in regulating cell death in activated T cells, but the underlying mechanism is unclear. Here, we show that inhibition of autophagy via Beclin 1 gene deletion in T cells leads to rampant apoptosis in these cells upon TCR stimulation. Beclin 1-deficient mice fail to mount autoreactive T-cell responses and are resistant to experimental autoimmune encephalomyelitis. Compared with Th17 cells, Th1 cells are much more susceptible to cell death upon Beclin 1 deletion. Cell death proteins are highly increased in Beclin 1-deficient T cells and inhibition of caspases and genetic deletion of Bim reverse apoptosis. In addition, p62/sequestosome 1 binds to caspase-8 but does not control levels of procaspase-8 or other cell death-related proteins. These results establish a direct role of autophagy in inhibiting the programmed cell death through degradation of apoptosis proteins in activated T cells.
自噬被认为在调节活化 T 细胞的细胞死亡中起作用，但潜在的机制尚不清楚。在这里，我们表明，通过 Beclin 1 基因缺失抑制 T 细胞中的自噬，会导致 T 细胞在 TCR 刺激后发生猖獗的细胞凋亡。Beclin 1 缺陷型小鼠无法产生自身反应性 T 细胞反应，并且对实验性自身免疫性脑脊髓炎具有抗性。与 Th17 细胞相比，Th1 细胞在 Beclin 1 缺失时更容易发生细胞死亡。Beclin 1 缺陷型 T 细胞中细胞死亡蛋白高度增加，并且抑制半胱天冬酶和 Bim 的基因缺失可逆转细胞凋亡。此外，p62/自噬体 1 与 caspase-8 结合，但不控制 procaspase-8 或其他与细胞死亡相关的蛋白质的水平。这些结果确立了自噬通过降解活化 T 细胞中的凋亡蛋白直接抑制程序性细胞死亡的作用。
