Splicing factor SRSF1 controls autoimmune-related molecular pathways in regulatory T cells distinct from FoxP3.
Splicing factor SRSF1 controls autoimmune-related molecular pathways in regulatory T cells distinct from FoxP3.
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DOI：
10.1016/j.molimm.2022.10.017
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发表时间：
2022-11
影响因子：
3.6
通讯作者：
Michael F. Cassidy;Zachary T. Herbert;Vaishali R. Moulton
中科院分区：
文献类型：
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作者：
Michael F. Cassidy;Zachary T. Herbert;Vaishali R. Moulton
调节性T细胞（TCRs）对于维持免疫自身耐受至关重要，其功能受损会导致自身免疫性疾病。FoxP 3是TcB的主要转录调节因子，其突变导致人类的免疫失调、多内分泌病、肠病、X连锁（IPEX）综合征和小鼠的多器官自身免疫性疾病的早期致死性“皮屑”表型。我们最近确定了丝氨酸/丝氨酸丰富的剪接因子1（SRSF 1）作为一个不可或缺的调节细胞的稳态和功能。有趣的是，Treg条件性SRSF 1缺陷小鼠表现出早期致死性全身性自身免疫，伴有多器官炎症，让人想起皮屑小鼠。重要的是，SRSF 1在自身免疫性疾病系统性红斑狼疮（SLE）患者的T细胞中减少，并且低SRSF 1水平与疾病严重程度呈负相关。考虑到SRSF 1的Treg特异性缺陷与FoxP 3的缺陷/突变在小鼠中引起类似的严重自身免疫性疾病结果，我们的目的是评估由这两种不可或缺的调节蛋白控制的基因和分子途径。我们对Srsf 1基因敲除小鼠和两种Foxp 3突变小鼠（FoxP 3缺陷型Δ Foxp 3和Foxp 3 M370 I突变小鼠）的TcR转录组图谱进行了比较生物信息学分析。我们鉴定了132个Srsf 1-koT基因特有的差异表达基因（DEG），503个Foxp 3 M370 T基因特有的DEG，和1367个Δ Foxp 3 T基因特有的DEG。SRSF 1-koT家族特有的DEG基因集富集和途径分析表明，SRSF 1控制细胞因子和免疫应答途径。相反，FoxP 3控制着DNA复制和细胞周期的通路。除了不同的基因特征，我们在所有三种Treg突变体之间仅鉴定出30个共享基因，主要是促进细胞因子和免疫防御途径。突出的基因包括趋化因子CXCR 6和CCL 1以及检查点抑制剂FASLG和PDCD 1。因此，我们证明，SRSF 1和FoxP 3控制共同的和不同的分子途径参与自身免疫。我们的分析表明，SRSF 1控制着T细胞的关键免疫功能，有助于免疫耐受，其水平的扰动导致系统性自身免疫，其机制与FoxP 3在很大程度上不同。
Regulatory T cells (Tregs) are vital for maintaining immune self-tolerance, and their impaired function leads to autoimmune disease. Mutations in FoxP3, the master transcriptional regulator of Tregs, leads to immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome in humans and the early lethal “scurfy” phenotype with multi-organ autoimmune disease in mice. We recently identified serine/arginine-rich splicing factor 1 (SRSF1) as an indispensable regulator of Treg homeostasis and function. Intriguingly, Treg-conditional SRSF1-deficient mice exhibit early lethal systemic autoimmunity with multi-organ inflammation reminiscent of the scurfy mice. Importantly, SRSF1 is decreased in T cells from patients with the autoimmune disease systemic lupus erythematosus (SLE), and low SRSF1 levels inversely correlate with disease severity. Given that the Treg-specific deficiency of SRSF1 causes similarly profound autoimmune disease outcomes in mice as the deficiency/mutation in FoxP3, we aimed to evaluate the genes and molecular pathways controlled by these two indispensable regulatory proteins. We performed comparative bioinformatic analyses of transcriptomic profiles of Tregs fromSrsf1-knockout mice and twoFoxp3mutant mice––the FoxP3-deficient ΔFoxp3and theFoxp3 M370Imutant mice. We identified 132 differentially expressed genes (DEGs) unique toSrsf1-koTregs, 503 DEGs unique toFoxp3 M370ITregs, and 1367 DEGs unique to ΔFoxp3Tregs. Gene set enrichment and pathway analysis of DEGs unique toSrsf1-koTregs indicate that SRSF1 controls cytokine and immune response pathways. Conversely, FoxP3 controls pathways involved in DNA replication and cell cycle. Besides the distinct gene signatures, we identified only 30 shared genes between all three Treg mutants, mostly contributing to cytokine and immune defense pathways. Prominent genes included the chemokines CXCR6 and CCL1 and the checkpoint inhibitors FASLG and PDCD1. Thus, we demonstrate that SRSF1 and FoxP3 control common and distinct molecular pathways implicated in autoimmunity. Our analyses suggest that SRSF1 controls crucial immune functions in Tregs contributing to immune tolerance, and perturbations in its levels lead to systemic autoimmunityviamechanisms that are largely distinct from FoxP3.