Complement C1q binding protein regulates T cells' mitochondrial fitness to affect their survival, proliferation, and anti-tumor immune function.
Complement C1q binding protein regulates T cells' mitochondrial fitness to affect their survival, proliferation, and anti-tumor immune function.
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补体 C1q 结合蛋白可调节 T 细胞的线粒体适应性，从而影响其生存、增殖和抗肿瘤免疫功能。
DOI：
10.1111/cas.15261
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发表时间：
2022-03
期刊：
影响因子：
5.7
通讯作者：
Zheng J
中科院分区：
文献类型：
--
作者：
Tian H;Wang G;Wang Q;Zhang B;Jiang G;Li H;Chai D;Fang L;Wang M;Zheng J
T细胞的存活、增殖和抗肿瘤反应与其线粒体健康密切相关。补体C1 q结合蛋白（C1 QBP）通过调节线粒体代谢和形态来促进线粒体健康。然而，C1 QBP是否调节T细胞存活、增殖和抗肿瘤免疫功能仍不清楚。我们的数据表明，C1 QBP敲低诱导活性氧（ROS）的积累和线粒体膜电位的损失，损害T细胞线粒体的健身。与此同时，C1 QBP不足减少了抗凋亡蛋白（包括Bcl-2和Bcl-XL）的募集，并抑制了caspase-3活化和聚（ADP-核糖）聚合酶裂解，从而加速了T细胞凋亡过程。相反，C1 QBP敲低由于AKT/mTOR信号通路的抑制而使T细胞具有相对较弱的增殖。为了研究C1 QBP在抗肿瘤反应中的确切作用，对C1 QBP +/-和C1 QBP +/+小鼠皮下注射鼠MC 38细胞。我们发现，C1 QBP缺乏减弱了T细胞肿瘤浸润，并加重了肿瘤浸润性T淋巴细胞（TIL）耗竭。此外，我们进一步阐明了C1 QBP在嵌合抗原受体（CAR）T细胞免疫治疗中的潜在功能。我们的数据显示，C1 QBP +/− CAR T细胞表现出比相应的C1 QBP +/+ CAR T细胞相对较弱的抗肿瘤反应。鉴于C1 QBP敲低损害T细胞的抗凋亡能力、增殖以及抗肿瘤免疫功能，开发通过C1 QBP增强T细胞线粒体适应性的策略可能会优化相关免疫疗法的功效。C1 QBP敲低使T细胞易于凋亡，因为抗凋亡蛋白（包括Bcl-2和Bcl-XL）的积累较少，从而促进caspase-3活化和PARP裂解。C1 QBP敲低通过抑制AKT‐ mTORC 1信号通路损害T细胞增殖。C1 QBP缺陷延缓T细胞肿瘤浸润并加速肿瘤浸润性T细胞耗竭，从而降低其抗肿瘤免疫。
T cells survival, proliferation, and anti–tumor response are closely linked to their mitochondrial health. Complement C1q binding protein (C1QBP) promotes mitochondrial fitness through regulation of mitochondrial metabolism and morphology. However, whether C1QBP regulates T cell survival, proliferation, and anti–tumor immune function remains unclear. Our data demonstrated that C1QBP knockdown induced the accumulation of reactive oxygen species (ROS) and the loss of mitochondrial membrane potential to impair T cell mitochondrial fitness. At the same time, C1QBP insufficiency reduced the recruitment of the anti–apoptotic proteins, including Bcl‐2 and Bcl‐XL, and repressed caspase‐3 activation and poly (ADP‐ribose) polymerase cleavage, which consequently accelerated the T cell apoptotic process. In contrast, C1QBP knockdown rendered T cells with relatively weaker proliferation due to the inhibition of AKT/mTOR signaling pathway. To investigate the exact role of C1QBP in anti–tumor response, C1QBP+/− and C1QBP+/+ mice were given a subcutaneous injection of murine MC38 cells. We found that C1QBP deficiency attenuated T cell tumor infiltration and aggravated tumor‐infiltrating T lymphocytes (TIL) exhaustion. Moreover, we further clarified the potential function of C1QBP in chimeric antigen receptor (CAR) T cell immunotherapy. Our data showed that C1QBP+/− CAR T cells exhibited relatively weaker anti–tumor response than the corresponding C1QBP+/+ CAR T cells. Given that C1QBP knockdown impairs T cells’ anti–apoptotic capacity, proliferation as well as anti–tumor immune function, development of the strategy for potentiation of T cells’ mitochondrial fitness through C1QBP could potentially optimize the efficacy of the related immunotherapy. C1QBP knockdown renders T cells prone to apoptosis due to less accumulation of the anti–apoptotic proteins, including Bcl‐2 and Bcl‐XL, thus facilitating caspase‐3 activation and PARP cleavage. C1QBP knockdown impairs T cells’ proliferation through dampening of the AKT‐mTORC1 signaling pathway. C1QBP deficiency retards T cell tumor infiltration and aggravates tumor infiltrating T cell exhaustion, thereby decreasing their anti–tumor immunity.
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DOI：
10.1042/bj20121829
发表时间：
2013-08-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Hu M;Crawford SA;Henstridge DC;Ng IH;Boey EJ;Xu Y;Febbraio MA;Jans DA;Bogoyevitch MA
通讯作者：
Bogoyevitch MA
影响因子：
64.8
作者：
Cunningham, John T.;Rodgers, Joseph T.;Puigserver, Pere
通讯作者：
Puigserver, Pere
影响因子：
7.1
作者：
Fernandez-Marcos, Pablo J.;Auwerx, Johan
通讯作者：
Auwerx, Johan
DOI：
10.1038/nri3198
发表时间：
2012-04-20
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.3
作者：
Inamura, Kentaro;Yokouchi, Yusuke;Ishikawa, Yuichi
通讯作者：
Ishikawa, Yuichi