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 December 2, 2019; First 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

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 5

Rapamycin treatment reduces proinflammatory cytokine production by T cells and alleviates autoimmunity in Srsf1-cKO mice.

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Rapamycin treatment reduces proinflammatory cytokine production by T cel...
(A–D) Spleen cells from WT or Srsf1-cKO mice were cultured for 4 hours with PMA plus ionomycin in the presence of monensin. Rapamycin (1 nM or 10 nM) was added for the duration of cultures. Cells were collected, surface stained, fixed, and permeabilized for intracellular cytokine staining. (A and C) Plots show IL-17 and IFN-γ intracellular staining gated on live CD4+ T cells. (B) Graphs show data from n = 8 mice in 7 independent experiments. (D) Graph shows data from n = 15 mice each in 10 independent experiments. (E–H) Rapamycin (2 mg/kg) or PBS was administered to WT and Srsf1-cKO mice by intraperitoneal injection once every 2 days for 4 weeks (F and G) or every day for 1 week (E and H). (E) Spleen cells were cultured with anti-CD3 (2 μg/mL) and anti-CD28 (2 μg/mL) for 24 hours and IL-17A measured in the supernatants by ELISA. Data are shown as fold values normalized to controls (n = 5 mice in 2 independent experiments). (F) Spleen cells were analyzed by flow cytometry, and graph shows the frequency of Tfh cells in spleen (n = 5–6 mice in 2 independent experiments). (G) Serum was collected and autoantibodies measured by ELISA (n = 5–6 mice in 2 independent experiments). (H) Cells from kidneys were analyzed by flow cytometry, and graph shows the frequency of T cells in kidneys (n = 5 mice in 2 independent experiments). One-way ANOVA with Bonferroni correction (B, D, E, and F); 2-tailed unpaired t test (G and H); *P < 0.05, **P < 0.005; mean ± SEM.