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Splicing factor SRSF1 controls T cell hyperactivity and systemic autoimmunity
Takayuki Katsuyama, … , George C. Tsokos, Vaishali R. Moulton
Takayuki Katsuyama, … , George C. Tsokos, Vaishali R. Moulton
Published September 5, 2019
Citation Information: J Clin Invest. 2019;129(12):5411-5423. https://doi.org/10.1172/JCI127949.
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Research Article Autoimmunity Immunology

Splicing factor SRSF1 controls T cell hyperactivity and systemic autoimmunity

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Abstract

Systemic lupus erythematosus (SLE) is a devastating autoimmune disease in which hyperactive T cells play a critical role. Understanding molecular mechanisms underlying the T cell hyperactivity will lead to identification of specific therapeutic targets. Serine/arginine-rich splicing factor 1 (SRSF1) is an essential RNA-binding protein that controls posttranscriptional gene expression. We have demonstrated that SRSF1 levels are aberrantly decreased in T cells from patients with SLE and that they correlate with severe disease, yet the role of SRSF1 in T cell physiology and autoimmune disease is largely unknown. Here we show that T cell–restricted Srsf1-deficient mice develop systemic autoimmunity and lupus-nephritis. Mice exhibit increased frequencies of activated/effector T cells producing proinflammatory cytokines, and an elevated T cell activation gene signature. Mechanistically, we noted increased activity of the mechanistic target of rapamycin (mTOR) pathway and reduced expression of its repressor PTEN. The mTOR complex 1 (mTORC1) inhibitor rapamycin suppressed proinflammatory cytokine production by T cells and alleviated autoimmunity in Srsf1-deficient mice. Of direct clinical relevance, PTEN levels correlated with SRSF1 in T cells from patients with SLE, and SRSF1 overexpression rescued PTEN and suppressed mTORC1 activation and proinflammatory cytokine production. Our studies reveal the role of a previously unrecognized molecule, SRSF1, in restraining T cell activation, averting the development of autoimmune disease, and acting as a potential therapeutic target for lupus.

Authors

Takayuki Katsuyama, Hao Li, Denis Comte, George C. Tsokos, Vaishali R. Moulton

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Figure 3

Transcriptomics analysis of CD4+ Teff cells from Srsf1-cKO mice reveals an elevated T cell activation gene signature.

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Transcriptomics analysis of CD4+ Teff cells from Srsf1-cKO mice reveals ...
(A) CD4+ Teff cells were generated as follows. Naive CD4+ T cells were sorted from spleens of WT and Srsf1-cKO mice (n = 3 each), and stimulated with anti-CD3 (0.5 μg/mL) and anti-CD28 (1.0 μg/mL) for 72 hours. RNA-sequencing data analysis shows differentially expressed (DE) genes with fold change (FC) differences at P < 0.05. (B) GO terms enrichment map of DE genes. The size of the red circles indicates the number of genes within a given pathway, and the color represents the P values relative to the other displayed terms. Outlines (added manually) indicate groups of similar GO terms. (C) Heatmap showing average expression of DE cytokine genes in WT and Srsf1-cKO mice.
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