Ncoa2通过上调PGC-1α的关键线粒体功能，促进CD8+T细胞介导的抗肿瘤免疫，从而刺激T细胞的活化。
Ncoa2 promotes CD8+ T cell-mediated anti-tumor immunity by stimulating T-cell activation via upregulation of PGC-1α critical for mitochondrial function.
发表日期：2023 Aug 04
作者：
Xiancai Zhong, Hongmin Wu, Ching Ouyang, Wencan Zhang, Yun Shi, Yi-Chang Wang, David K Ann, Yousang Gwack, Weirong Shang, Zuoming Sun
来源：
Cellular & Molecular Immunology
摘要：
核受体协同激活因子2（Ncoa2）是Ncoa家族的共激活因子之一，我们先前的研究表明Ncoa2调控诱导性调节性T细胞的分化。然而，目前不清楚Ncoa2是否在CD8+ T细胞功能中起作用。在本研究中，我们展示了Ncoa2通过上调PGC-1α表达来增强线粒体功能，从而促进CD8+ T细胞介导的肿瘤免疫应答。缺乏T细胞内Ncoa2的小鼠（Ncoa2fl/fl/CD4Cre）在人工移植的MC38肿瘤模型中显示出免疫应答缺陷，伴随着显著减少的肿瘤浸润CD8+ T细胞和降低的IFNγ产生。一致地，从Ncoa2fl/fl/CD4Cre小鼠中获取的CD8+ T细胞，在移植到Rag1-/-小鼠后无法排斥肿瘤。此外，对TCR刺激的反应中，Ncoa2fl/fl/CD4Cre CD8+ T细胞未能增加线粒体质量，显示出受损的氧化磷酸化以及PGC-1α表达下降，后者是线粒体生成和功能的主要调控因子。机械地讲，T细胞活化诱导的CREB磷酸化触发Ncoa2的招募，从而促使其与增强子结合，进而刺激PGC-1α的表达。在Ncoa2fl/fl/CD4Cre CD8+ T细胞中强制表达PGC-1α可恢复线粒体功能、T细胞活化、IFNγ产生和抗肿瘤免疫力。本研究为基于Ncoa2调节的治疗策略在调节CD8+ T细胞介导的抗肿瘤免疫应答方面提供了新的线索。
Nuclear receptor coactivator 2 (Ncoa2) is a member of the Ncoa family of co-activators, and we previously showed that Ncoa2 regulates the differentiation of induced regulatory T cells. However, it remains unknown if Ncoa2 plays a role in CD8+ T-cell function. Here, we show that Ncoa2 promotes CD8+ T cell-mediated immune responses against tumors by stimulating T-cell activation via upregulating PGC-1α expression to enhance mitochondrial function. Mice deficient in Ncoa2 in T cells (Ncoa2fl/fl/CD4Cre) displayed defective immune responses against implanted MC38 tumors, which associated with significantly reduced tumor-infiltrating CD8+ T cells and decreased IFNγ production. Consistently, CD8+ T cells from Ncoa2fl/fl/CD4Cre mice failed to reject tumors after adoptive transfer into Rag1-/- mice. Further, in response to TCR stimulation, Ncoa2fl/fl/CD4Cre CD8+ T cells failed to increase mitochondrial mass, showed impaired oxidative phosphorylation, and had lower expression of PGC-1α, a master regulator of mitochondrial biogenesis and function. Mechanically, T cell activation-induced phosphorylation of CREB triggered the recruitment of Ncoa2 to bind to enhancers, thus, stimulating PGC-1α expression. Forced expression of PGC-1α in Ncoa2fl/fl/CD4Cre CD8+ T cells restored mitochondrial function, T-cell activation, IFNγ production, and anti-tumor immunity. This work informs the development of Ncoa2-based therapies that modulate CD8+ T cell-mediated anti-tumor immune responses.