Abstract

AMBRA1 (activating molecule in Beclin1-regulated autophagy) is a member of the BECN1 (BECLIN1) protein complex, and it plays a role in autophagy, cell death, tumorigenesis and proliferation. We recently reported that on T-cell receptor (TCR) stimulation, AMBRA1 controlled both autophagy and the cell cycle with metabolic regulation. Accumulating evidence has shown that autophagy and metabolic control are pivotal for T-cell activation, clonal expansion and effector/memory cell fate decision. However, it is unknown whether AMBRA1 is involved in T-cell function under physiological conditions. We found that T cells in Ambra1-conditional knockout (cKO) mice induced an exacerbated graft versus host response when they were transplanted into allogeneic BALB/c mice. Furthermore, Ambra1-deficient T cells showed increased proliferation and cytotoxic capability toward specific antigens in response to in vivo stimulation using allogeneic spleen cells. This enhanced immune response mainly contributed to naive T-cell hyperactivity. The T-cell hyperactivity observed in this study was similar to those in some metabolic factor-deficient mice, but not those in other pro-autophagic factor-deficient mice. Under the static condition, however, naive T cells were reduced in Ambra1-cKO mice, the same as in pro-autophagic factor-deficient mice. Collectively, these results suggested that AMBRA1 was involved in regulating T cell-mediated immune responses through autophagy-dependent and -independent mechanisms.

中文翻译：

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AMBRA1控制抗原驱动的幼稚T细胞活化和增殖

摘要

AMBRA1（Beclin1 调节的自噬中的激活分子）是 BECN1（BECLIN1）蛋白复合物的成员，在自噬、细胞死亡、肿瘤发生和增殖中发挥作用。我们最近报道了在 T 细胞受体 (TCR) 刺激下，AMBRA1 通过代谢调节控制自噬和细胞周期。越来越多的证据表明，自噬和代谢控制对于 T 细胞活化、克隆扩增和效应/记忆细胞命运决定至关重要。然而，尚不清楚 AMBRA1 是否参与生理条件下的 T 细胞功能。我们发现 Ambra1 条件性敲除 (cKO) 小鼠中的 T 细胞在移植到同种异体 BALB/c 小鼠中时会诱导加剧的移植物抗宿主反应。此外，Ambra1缺陷型 T 细胞响应使用同种异体脾细胞的体内刺激，显示出对特定抗原的增殖和细胞毒性能力增加。这种增强的免疫反应主要导致幼稚 T 细胞过度活跃。在这项研究中观察到的 T 细胞过度活跃与一些代谢因子缺陷小鼠的相似，但与其他自噬因子缺陷小鼠的相似。然而，在静态条件下， Ambra1 -cKO 小鼠的幼稚 T 细胞减少，与自噬因子缺乏的小鼠相同。总的来说，这些结果表明 AMBRA1 通过自噬依赖和非依赖机制参与调节 T 细胞介导的免疫反应。