T细胞
CD8型
生物
细胞毒性T细胞
线粒体生物发生
细胞生物学
T细胞受体
癌症研究
免疫系统
线粒体
免疫学
生物化学
体外
作者
Xiancai Zhong,Hongmin Wu,Ching Ouyang,Wencan Zhang,Yun Shi,Yi-Chang Wang,David K. Ann,Yousang Gwack,Weirong Shang,Zuoming Sun
标识
DOI:10.1158/2326-6066.cir-23-0092
摘要
Abstract Nuclear receptor coactivator 2 (Ncoa2) is a member of the Ncoa family of coactivators, 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 antitumor immunity. This work informs the development of Ncoa2-based therapies that modulate CD8+ T cell–mediated antitumor immune responses.
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