The RNA-binding protein serine/arginine-rich splicing factor 1 (SRSF1) restrains T cell hyperactivity and systemic autoimmunity in systemic lupus erythematosus (SLE), according to a new study. The researchers found that in T cells, SRSF1 suppresses the activity of the mechanistic target of rapamycin (mTOR) pathway by promoting the expression of PTEN (a negative regulator of the mTOR pathway), but that this braking system is potentially dysregulated in SLE.

Credit: N. Smith/Springer Nature Limited

“Patients with SLE and other autoimmune diseases have an overactive immune response,” explains corresponding author Vaishali Moulton. “Defects in signalling and gene regulation in T cells from patients with SLE are linked to the hyperactive phenotype of these cells, which makes them produce high amounts of aberrant inflammatory cytokines.”

Previous findings had implicated SRSF1 in T cell dysfunction in SLE. To investigate this link further, the researchers generated mice with T cell-specific deletion of Srsf1. The mice developed systemic autoimmunity, as indicated by the presence of circulating SLE-associated autoantibodies and kidney disease resembling lupus nephritis.

Notably, the T cells from these mice had a hyperactive phenotype and produced pro-inflammatory cytokines (including IL-17, IL-4 and IFNγ). Furthermore, the activity of mTOR was increased in these cells, whereas the expression of PTEN was downregulated. Using a luciferase report assay, the researchers found that SRSF1 post-transcriptionally controlled the expression of PTEN.

Treatment with rapamycin, an mTOR pathway inhibitor, reduced the production of pro-inflammatory cytokines by SRSF1-deficient T cells in vitro. Furthermore, rapamycin treatment reduced serum autoantibodies titres and inhibited T cell infiltration into the kidneys in SRSF1-deficient mice.

Interestingly, T cells from patients with SLE expressed low levels of PTEN that correlated with low levels of SRSF1. Transient transfection of T cells from patients with SLE with an SRSF1-expressing vector increased the expression of PTEN, reduced the activity of mTOR and decreased the production of IL-17 and IFNγ.

the T cells … had a hyperactive phenotype and produced pro-inflammatory cytokines

“These findings open up an exciting unexplored avenue for future studies and could pave the path for new molecules and pathways as targets for therapy or biomarkers,” concludes Moulton.