NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA.
Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA, USA.
Yale J Biol Med. 2023 Dec 29;96(4):467-473. doi: 10.59249/AXGU7370. eCollection 2023 Dec.
T cells undergo extensive chromatin remodeling over several days following stimulation through the T cell receptor. However, the kinetics and gene loci targeted by early remodeling events within the first 24 hours of T cell priming to orchestrate effector differentiation have not been well described. We identified that chromatin accessibility is rapidly and extensively remodeled within 1 hour of stimulation of naïve CD8 T cells, leading to increased global chromatin accessibility at many effector T cell-associated genes that are enriched for AP-1, early growth response (EGR), and nuclear factor of activated T cells (NFAT) binding sites, but this short duration of stimulation is insufficient for commitment to clonal expansion . Sustained 24-hour stimulation led to further chromatin remodeling and was sufficient to enable clonal expansion. These data suggest that the duration of antigen receptor signaling is intimately coupled to chromatin remodeling and activation of genes involved in effector cell differentiation and highlight a potential mechanism that helps CD8 T cells discriminate between foreign- and self-antigens.
T 细胞在受到 T 细胞受体刺激后的几天内经历广泛的染色质重塑。然而,在 T 细胞初始激活后最初 24 小时内,早期重塑事件的动力学和靶向的基因座,以协调效应器分化,尚未得到很好的描述。我们发现,在刺激幼稚 CD8 T 细胞后 1 小时内,染色质可及性迅速而广泛地重塑,导致许多与效应 T 细胞相关的基因的全局染色质可及性增加,这些基因富含 AP-1、早期生长反应 (EGR) 和激活 T 细胞的核因子 (NFAT) 结合位点,但这种短暂的刺激不足以促使克隆扩增。持续 24 小时的刺激导致进一步的染色质重塑,并足以实现克隆扩增。这些数据表明,抗原受体信号的持续时间与染色质重塑以及参与效应细胞分化的基因的激活密切相关,并强调了一种潜在的机制,帮助 CD8 T 细胞区分外来抗原和自身抗原。
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