Splicing factor SRSF1 controls T cell hyperactivity and systemic autoimmunity

J Clin Invest. 2019 Dec 2;129(12):5411-5423. doi: 10.1172/JCI127949.


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.

Keywords: Autoimmunity; Cytokines; Immunology; Lupus; T cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmunity*
  • Cytokines / biosynthesis
  • Humans
  • Lupus Nephritis / etiology
  • Lymphocyte Activation
  • Mechanistic Target of Rapamycin Complex 1 / physiology
  • Mice
  • Mice, Inbred C57BL
  • PTEN Phosphohydrolase / analysis
  • PTEN Phosphohydrolase / genetics
  • Serine-Arginine Splicing Factors / physiology*
  • Signal Transduction
  • Sirolimus / pharmacology
  • T-Lymphocytes / immunology*
  • TOR Serine-Threonine Kinases / physiology


  • Cytokines
  • Srsf1 protein, mouse
  • Serine-Arginine Splicing Factors
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases
  • PTEN Phosphohydrolase
  • Sirolimus