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

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 7

PTEN is decreased in T cells from patients with SLE and correlates with SRSF1 levels.

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PTEN is decreased in T cells from patients with SLE and correlates with ...
SRSF1 overexpression increases PTEN, suppresses mTORC1 activity, and reduces proinflammatory cytokine production. (A and B) Peripheral blood T cells were isolated from patients with SLE and normal (N) healthy control individuals. Total protein was immunoblotted for PTEN, SRSF1, and β-actin. (A) Data are from 1 representative of 10 independent experiments. Graph shows relative quantitation by densitometry (n = 14 SRSF1 low and n = 12 SRSF1 normal patients). (B) Graph shows a linear correlation between relative PTEN and SRSF1 expression. (C) Peripheral blood T cells were isolated from patients with SLE and transfected with empty vector (EV) or SRSF1 overexpression plasmid (pSrsf1). At 16 to 18 hours after transfections, SLE T cells were stimulated with anti-CD3, anti-CD28, and crosslinker for 5 minutes. Total protein was immunoblotted for PTEN. Data are from 1 representative of 5 independent experiments (n = 10). Graph shows relative quantitation by densitometry. (D) Total protein was immunoblotted for pS6 and total S6 in stimulated SLE T cells after transfection as described in C. Data are from 1 representative of 4 independent experiments (n = 4). Graph shows relative quantitation by densitometry. (E) At 16 to 18 hours after transfection, cells were stimulated with PMA and ionomycin in the presence of monensin. After 4 hours, cytokine production was analyzed by flow cytometry. Graphs show quantitation of cytokine data (n = 8). Paired t test, *P < 0.05, mean ± SEM. The mTOR pathway via the regulation of PTEN expression. In T cells from KO mice and patients with SLE, reduced SRSF1 levels contribute to reduced PTEN levels and increased activity of the mTOR pathway. Rapamycin blocks the mTORC1 pathway and reduces proinflammatory cytokines.