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 at Dana-Farber Cancer Institute, Boston, MA, United States.
Mol Immunol. 2022 Jan;141:94-103. doi: 10.1016/j.molimm.2021.11.008. Epub 2021 Nov 25.
Systemic autoimmune diseases are characterized by hyperactive effector T cells (Teffs), aberrant cytokines and chemokines, and dysfunctional regulatory T cells (Tregs). We previously uncovered new roles for serine/arginine-rich splicing factor 1 (SRSF1) in the control of genes involved in T cell signaling and cytokine production in human T cells. SRSF1 levels are decreased in T cells from patients with systemic lupus erythematosus (SLE), and low levels correlate with severe disease. Moreover, T cell-conditional Srsf1-deficient mice recapitulate the autoimmune phenotype, exhibiting CD4 T cell hyperactivity, dysfunctional Tregs, systemic autoimmunity, and tissue inflammation. However, the role of SRSF1 in controlling molecular programs in Teffs and Tregs and how these pathways are implicated in autoimmunity is not known. Here, by comparative bioinformatics analysis, we demonstrate that SRSF1 controls largely distinct gene programs in Tregs and Teffs in vivo. SRSF1 regulates 189 differentially expressed genes (DEGs) unique to Tregs, 582 DEGs unique to Teffs, and 29 DEGs shared between both. Shared genes included IL-17A, IL-17F, CSF1, CXCL10, and CXCR4, and were highly enriched for inflammatory response and cytokine-cytokine receptor interaction pathways. SRSF1 controls distinct pathways in Tregs, which include chemokine signaling and immune cell differentiation, compared with pathways in Teffs, which include cytokine production, T cell homeostasis, and activation. We identified putative mRNA binding targets of SRSF1 which include CSF1, CXCL10, and IL-17F. Finally, comparisons with transcriptomics profiles from lupus-prone MRL/lpr mice reveal that SRSF1 controls genes and pathways implicated in autoimmune disease. The target genes of SRSF1 and putative binding targets we discovered, have known roles in systemic autoimmunity. Our findings suggest that SRSF1 controls distinct molecular pathways in Tregs and Teffs and aberrant SRSF1 levels may contribute to their dysfunction and immunopathogenesis of systemic autoimmune disease.
系统性自身免疫性疾病的特征是效应 T 细胞（Teffs）过度活跃、细胞因子和趋化因子异常以及调节性 T 细胞（Tregs）功能障碍。我们之前发现丝氨酸/精氨酸丰富剪接因子 1（SRSF1）在控制人类 T 细胞信号转导和细胞因子产生相关基因方面具有新的作用。系统性红斑狼疮（SLE）患者的 T 细胞中 SRSF1 水平降低，低水平与疾病严重程度相关。此外，T 细胞条件性 Srsf1 缺陷小鼠重现自身免疫表型，表现为 CD4 T 细胞过度活跃、Tregs 功能障碍、全身自身免疫和组织炎症。然而，SRSF1 控制 Teffs 和 Tregs 中分子程序的作用以及这些途径如何与自身免疫相关尚不清楚。在这里，通过比较生物信息学分析，我们证明 SRSF1 在体内控制 Tregs 和 Teffs 中差异表达基因（DEGs）的差异表达。SRSF1 调节 Tregs 中独特的 189 个差异表达基因（DEGs），Teffs 中独特的 582 个 DEGs，以及两者之间共享的 29 个 DEGs。共享基因包括 IL-17A、IL-17F、CSF1、CXCL10 和 CXCR4，并且高度富集于炎症反应和细胞因子-细胞因子受体相互作用途径。与 Teffs 中的细胞因子产生、T 细胞稳态和激活途径相比，SRSF1 在 Tregs 中控制独特的途径，包括趋化因子信号和免疫细胞分化。我们鉴定了 SRSF1 的潜在 mRNA 结合靶标，包括 CSF1、CXCL10 和 IL-17F。最后，与狼疮易感 MRL/lpr 小鼠的转录组学谱进行比较表明，SRSF1 控制自身免疫性疾病相关的基因和途径。SRSF1 控制的基因和我们发现的潜在结合靶标在系统性自身免疫中具有已知作用。我们的研究结果表明，SRSF1 在 Tregs 和 Teffs 中控制不同的分子途径，异常的 SRSF1 水平可能导致它们功能障碍和系统性自身免疫性疾病的免疫发病机制。
