# Foxp3DEx2 isoform expression leads to Treg dysfunction and SLE

> **NIH NIH R21** · BENAROYA RESEARCH INST AT VIRGINIA MASON · 2021 · $261,150

## Abstract

Project Summary
 Regulatory T (Treg) cells play a central role in maintaining immune system homeostasis and
modulating immune responses. Foxp3 is a master regulator of Treg development and function. FOXP3
mutations in patients with IPEX, which result in a deficiency in Tregs, result in lethal autoimmunity, similar to
the disease observed in Foxp3 deficient mice. While highly conserved in both amino acid sequence and gene
structure, one difference between humans and mice is that the human FOXP3 gene encodes two major
alternatively spliced isoforms: a full length version that uses all 10 exons (FOXP3-FL, the only isoform in mice)
and a shorter isoform lacking sequences shown to be important in regulating Th17 differentiation. Recent
studies have shown that Tregs from patients with some autoimmune diseases express increased levels of the
∆E2 isoform compared to those from healthy donors. Consistent with this finding, we have found that Tregs
from SLE patients have increased expression of the FOXP3∆Ex2 isoform.
 To study the role of the ∆E2 isoform in Treg function we generated a new mouse strain with Foxp3
exon 2 deletion. Interestingly, we found that Foxp3∆E2 mice develop hallmark features of SLE, including anti-
DNA and anti-nuclear autoantibodies, increased number and size of spontaneous germinal centers and kidney
deposition of antibody complexes, by 4-5 weeks of age. However, these mice do not develop full-blown
disease and have a normal life span. Our central hypothesis is that the region encoded by exon 2 of
Foxp3 gene is critical for normal Treg identity and function. To test this hypothesis we will take 2
approaches. First, we will determine the levels of FOXP3-FL and -∆Ex2-expressing Tregs in healthy human
subjects and subjects with autoimmune disease. These studies will be complemented with studies using mice
containing varying ratios of Tregs expressing each isoform. Second, we test the hypothesis that Tregs
expressing FOXP3-∆Ex2 have a reduced ability to regulate effector T cell activation, using both human Treg
clones and a mouse transfer colitis model. Together these studies will allow us to gain important information
on the expression of FOXP3∆Ex2 and the function of Tregs expressing this isoform.

## Key facts

- **NIH application ID:** 10147509
- **Project number:** 1R21AI152444-01A1
- **Recipient organization:** BENAROYA RESEARCH INST AT VIRGINIA MASON
- **Principal Investigator:** Steven F Ziegler
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $261,150
- **Award type:** 1
- **Project period:** 2021-03-03 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10147509

## Citation

> US National Institutes of Health, RePORTER application 10147509, Foxp3DEx2 isoform expression leads to Treg dysfunction and SLE (1R21AI152444-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10147509. Licensed CC0.

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