Department of Immunology, Mayo Clinic, Rochester, United States.
Division of Rheumatology, Department of Medicine, Mayo Clinic, Rochester, United States.
Elife. 2021 Dec 2;10:e70978. doi: 10.7554/eLife.70978.
After antigenic activation, quiescent naive CD4 T cells alter their metabolism to proliferate. This metabolic shift increases production of nucleotides, amino acids, fatty acids, and sterols. Here, we show that histone deacetylase 3 (HDAC3) is critical for activation of murine peripheral CD4 T cells. HDAC3-deficient CD4 T cells failed to proliferate and blast after in vitro TCR/CD28 stimulation. Upon T-cell activation, genes involved in cholesterol biosynthesis are upregulated while genes that promote cholesterol efflux are repressed. HDAC3-deficient CD4 T cells had reduced levels of cellular cholesterol both before and after activation. HDAC3-deficient cells upregulate cholesterol synthesis appropriately after activation, but fail to repress cholesterol efflux; notably, they overexpress cholesterol efflux transporters ABCA1 and ABCG1. Repression of these genes is the primary function for HDAC3 in peripheral CD4 T cells, as addition of exogenous cholesterol restored proliferative capacity. Collectively, these findings demonstrate HDAC3 is essential during CD4 T-cell activation to repress cholesterol efflux.
抗原激活后，静止的幼稚 CD4 T 细胞改变其代谢以增殖。这种代谢转变增加了核苷酸、氨基酸、脂肪酸和固醇的产生。在这里，我们表明组蛋白去乙酰化酶 3（HDAC3）对于激活小鼠外周 CD4 T 细胞至关重要。缺乏 HDAC3 的 CD4 T 细胞在体外 TCR/CD28 刺激后无法增殖和发生细胞裂解。在 T 细胞激活后，参与胆固醇生物合成的基因上调，而促进胆固醇外排的基因受到抑制。缺乏 HDAC3 的 CD4 T 细胞在激活前后的细胞胆固醇水平降低。缺乏 HDAC3 的细胞在激活后适当地上调胆固醇合成，但不能抑制胆固醇外排；值得注意的是，它们过度表达胆固醇外排转运蛋白 ABCA1 和 ABCG1。这些基因的抑制是 HDAC3 在周围 CD4 T 细胞中的主要功能，因为添加外源性胆固醇恢复了增殖能力。总之，这些发现表明 HDAC3 在 CD4 T 细胞激活过程中对于抑制胆固醇外排是必不可少的。
