# Role of splicing factor SRSF1 in T cell function and autoimmunity

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $326,355

## Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown cause, which mainly afflicts
women in their childbearing years and affects multiple organs including the skin and joints with complications in
vital organs such as kidneys and brain. T cell dysfunction due to altered intracellular signaling, gene
expression, and function, is thought to be central in the pathogenesis of this disease. The applicant used a
discovery approach and identified a protein namely serine arginine-rich splicing factor 1 (SRSF1) as a
regulator of a critical signaling gene - CD3 zeta chain, in human T cells. Furthermore, the applicant showed
that SRSF1 is a novel regulator of interleukin (IL)-2, a cytokine necessary for T cell function. Interestingly, T
cells from several patients with SLE have reduced levels of SRSF1 and its overexpression improves IL-2
production. This suggests that aberrant SRSF1 expression may contribute to defective T cell function and
therefore to disease pathophysiology. To advance these concepts, and to determine the role of SRSF1 in the
immune system within a whole organism, the applicant has generated mice lacking the Srsf1 gene
conditionally in T cells. Intriguingly, this mouse has defects in T cell phenotype and function, including reduced
expression of CD3 zeta chain, reduced IL-2, and increased proinflammatory IL-17 cytokine production. The
mouse develops autoantibodies and signs of kidney disease. Interestingly, estrogen downregulates SRSF1
expression levels in T cells from healthy women but not men. Based on the preliminary evidence generated in
human T cells and in the T cell Srsf1-deficient mouse, the hypothesis is that SRSF1 is a critical regulator of T
cell function and its deficiency promotes the expression of autoimmunity and related pathology. To test this
hypothesis the applicant will - 1) Determine how SRSF1 controls T cell homeostasis and function and enables
development of autoimmunity and related pathology 2) Determine how T cell-specific deletion of SRSF1
influences spontaneous and induced autoimmune disease and 3) Determine the role and regulation of SRSF1
in T cells from SLE patients and normal subjects. The applicant proposes the characterization of a novel
mouse, which will help define the role of SRSF1 in T cell function and the expression of autoimmunity and
related pathology using cellular and molecular immunology approaches. In parallel, studies proposed in human
T cells will provide a molecular link to hormonal aspects of SLE pathogenesis. This proposal is well within the
scope and goals of the applicant's currently funded NIAMS K01 award, which is to develop to an independent
investigator.

## Key facts

- **NIH application ID:** 9993321
- **Project number:** 5R01AR068974-05
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Iannis Elias Adamopoulos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $326,355
- **Award type:** 5
- **Project period:** 2016-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9993321

## Citation

> US National Institutes of Health, RePORTER application 9993321, Role of splicing factor SRSF1 in T cell function and autoimmunity (5R01AR068974-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9993321. Licensed CC0.

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