Splicing factor SRSF1 controls T cell homeostasis and its decreased levels are linked to lymphopenia in systemic lupus erythematosus

Takayuki Katsuyama, Ignacio Juarez Martin-Delgado, Suzanne M. Krishfield, Vasileios C. Kyttaris, Vaishali R. Moulton

Research output: Contribution to journalArticlepeer-review

Abstract

OBJECTIVE: Lymphopenia is a frequent clinical manifestation and risk factor for infections in SLE, but the underlying mechanisms are not fully understood. We previously identified novel roles for the RNA-binding protein serine arginine-rich splicing factor 1 (SRSF1) in the control of genes involved in signalling and cytokine production in human T cells. SRSF1 is decreased in T cells from patients with SLE and associates with severe disease. Because SRSF1 controls the expression of apoptosis-related genes, we hypothesized that SRSF1 controls T cell homeostasis and, when reduced, leads to lymphopenia. METHODS: We evaluated SRSF1 expression in T cells from SLE patients by immunoblots and analysed its correlation with clinical parameters. T cell conditional Srsf1 knockout mice were used to evaluate lymphoid cells and apoptosis by flow cytometry. Quantitative PCR and immunoblots were used to assess Bcl-xL mRNA and protein expression. SRSF1 overexpression was performed by transient transfections by electroporation. RESULTS: We found that low SRSF1 levels correlated with lymphopenia in SLE patients. Selective deletion of Srsf1 in T cells in mice led to T cell lymphopenia, with increased apoptosis and decreased expression of the anti-apoptotic Bcl-xL. Lower SRSF1 expression correlated with low Bcl-xL levels in T cells and lower Bcl-xL levels associated with lymphopenia in SLE patients. Importantly, overexpression of SRSF1 rescued survival of T cells from patients with SLE. CONCLUSION: Our studies uncovered a previously unrecognized role for SRSF1 in the control of T cell homeostasis and its reduced expression as a molecular defect that contributes to lymphopenia in systemic autoimmunity.

Original languageEnglish
Pages (from-to)2146-2155
Number of pages10
JournalRheumatology
Volume59
Issue number8
DOIs
Publication statusPublished - Aug 1 2020
Externally publishedYes

Keywords

  • Bcl-xL
  • homeostasis
  • lymphopenia
  • SRSF1
  • systemic lupus erythematosus
  • T cells

ASJC Scopus subject areas

  • Rheumatology
  • Pharmacology (medical)

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