Division of Rheumatology and Clinical Immunology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States; Tufts University School of Medicine, Boston, MA, United States.
Molecular Biology Core Facilities, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, United States.
Mol Immunol. 2022 Dec;152:140-152. doi: 10.1016/j.molimm.2022.10.017. Epub 2022 Nov 8.
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 from Srsf1-knockout mice and two Foxp3 mutant mice--the FoxP3-deficient ΔFoxp3 and the Foxp3 M370I mutant mice. We identified 132 differentially expressed genes (DEGs) unique to Srsf1-ko Tregs, 503 DEGs unique to Foxp3 M370I Tregs, and 1367 DEGs unique to ΔFoxp3 Tregs. Gene set enrichment and pathway analysis of DEGs unique to Srsf1-ko Tregs 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 autoimmunity via mechanisms that are largely distinct from FoxP3.
调节性 T 细胞（Tregs）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。FoxP3 是 Tregs 的主要转录调控因子，其突变会导致免疫失调、多发性内分泌腺病、肠病、X 连锁（IPEX）综合征在人类中，以及早期致命的“scurfy”表型伴多器官自身免疫性疾病在小鼠中。我们最近发现丝氨酸/精氨酸丰富的剪接因子 1（SRSF1）是 Treg 稳态和功能不可或缺的调节剂。有趣的是，Treg 条件性 SRSF1 缺陷小鼠表现出早期致死性全身自身免疫性疾病，伴有多器官炎症，类似于 scurfy 小鼠。重要的是，患有自身免疫性疾病系统性红斑狼疮（SLE）的患者 T 细胞中的 SRSF1 减少，并且 SRSF1 水平与疾病严重程度呈负相关。鉴于 Treg 特异性 SRSF1 缺陷在小鼠中引起的自身免疫性疾病结果与 FoxP3 的缺陷/突变相似，我们旨在评估这两种不可或缺的调节蛋白所控制的基因和分子途径。我们对 Srsf1 敲除小鼠和两种 Foxp3 突变小鼠（Foxp3 缺陷型 ΔFoxp3 和 Foxp3 M370I 突变型）的 Treg 转录组谱进行了比较生物信息学分析。我们鉴定出 132 个在 Srsf1-ko Tregs 中特异性差异表达的基因（DEGs），503 个在 Foxp3 M370I Tregs 中特异性差异表达的基因，以及 1367 个在 ΔFoxp3 Tregs 中特异性差异表达的基因。Srsf1-ko Tregs 中特异性差异表达基因的基因集富集和通路分析表明，SRSF1 控制细胞因子和免疫反应途径。相反，FoxP3 控制涉及 DNA 复制和细胞周期的途径。除了独特的基因特征外，我们还在所有三种 Treg 突变体之间鉴定出仅 30 个共享基因，主要与细胞因子和免疫防御途径有关。突出的基因包括趋化因子 CXCR6 和 CCL1 以及检查点抑制剂 FASLG 和 PDCD1。因此，我们证明 SRSF1 和 FoxP3 控制与自身免疫相关的共同和独特的分子途径。我们的分析表明，SRSF1 控制 Tregs 中至关重要的免疫功能，有助于免疫耐受，其水平的波动通过与 FoxP3 基本不同的机制导致全身自身免疫。
