胸腺细胞发育和谱系确定的潜在机制仍未完全了解,新出现的证据表明,RNA结合蛋白(RBP)与胸腺T细胞命运的控制密切相关。富含丝氨酸/精氨酸的剪接因子1(SRSF1),作为经典的拼接因子,是各种生物过程中基因表达的关键RBP。我们最近的研究表明,SRSF1通过在转录后调节T细胞调控基因网络在晚期胸腺细胞的发育中起重要作用,对支持胸腺细胞成熟的I型干扰素信号传导至关重要。这里,我们报告SRSF1也有助于CD8+T细胞命运的确定。通过SRSF1特异性消融CD4+CD8+双阳性(DP)胸腺细胞,我们发现SRSF1缺乏会损害晚期胸腺细胞的成熟,并减少CD4和CD8单阳性T细胞的输出。有趣的是,成熟CD4+与CD8+细胞的比例显著改变,CD8+谱系比CD4+谱系表现出更严重的缺陷,反映了SRSF1在CD8+T细胞命运决定中的特定功能。机械上,SRSF1缺陷细胞下调其Runx3的表达,Runx3是维持CD8单阳性(SP)胸腺细胞发育和谱系选择的关键转录调节因子。此外,Runx3的强制表达部分纠正了SRSF1缺陷的CD8+胸腺细胞成熟的缺陷。因此,我们的数据揭示了以前未知的SRSF1在CD8+细胞身份建立中的作用.
The underlying mechanisms of thymocyte development and lineage determination remain incompletely understood, and the emerging evidences demonstrated that RNA binding proteins (RBPs) are deeply involved in governing T cell fate in thymus. Serine/arginine-rich splicing factor 1 (SRSF1), as a classical splicing factor, is a pivotal RBP for gene expression in various biological processes. Our recent study demonstrated that SRSF1 plays essential roles in the development of late thymocytes by modulating the T cell regulatory gene networks post-transcriptionally, which are critical in response to type I interferon signaling for supporting thymocyte maturation. Here, we report SRSF1 also contributes to the determination of the CD8+ T cell fate. By specific ablation of SRSF1 in CD4+CD8+ double positive (DP) thymocytes, we found that SRSF1 deficiency impaired the maturation of late thymocytes and diminished the output of both CD4+ and CD8+ single positive T cells. Interestingly, the ratio of mature CD4+ to CD8+ cells was notably altered and more severe defects were exhibited in CD8+ lineage than those in CD4+ lineage, reflecting the specific function of SRSF1 in CD8+ T cell fate decision. Mechanistically, SRSF1-deficient cells downregulate their expression of Runx3, which is a crucial transcriptional regulator in sustaining CD8+ single positive (SP) thymocyte development and lineage choice. Moreover, forced expression of Runx3 partially rectified the defects in SRSF1-deficient CD8+ thymocyte maturation. Thus, our data uncovered the previous unknown role of SRSF1 in establishment of CD8+ cell identity.