4.5 Article

Splicing factor SRSF1 controls autoimmune-related molecular pathways in regulatory T cells distinct from FoxP3

期刊

MOLECULAR IMMUNOLOGY
卷 152, 期 -, 页码 140-152

出版社

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2022.10.017

关键词

Regulatory T cells; Autoimmune disease; SRSF1; Transcriptomics; Bioinformatics; Gene expression

资金

  1. National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01 AR068974]
  2. Rheumatology Research Foundation

向作者/读者索取更多资源

Regulatory T cells (Tregs) are crucial for maintaining immune self-tolerance, and their function can be impaired leading to autoimmune disease. SRSF1 and FoxP3 are two indispensable regulatory proteins in Tregs, controlling common and distinct molecular pathways related to cytokine, immune response, DNA replication, and cell cycle.
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 Tregspecific 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.Foxp3 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.Foxp3 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.

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