# FOXP3 ΔE2 Isoform in Treg Function and Pathophysiology of Lupus

> **NIH NIH R21** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $237,750

## Abstract

PROJECT SUMMARY
FOXP3 is a key transcription factor for the development and function of regulatory T cells (Tregs) and
amorphic mutations at this locus in humans and mice lead to systemic autoimmune diseases and allergic
symptoms. FOXP3 gene is highly conserved with 87% amino acid identity between humans and mice. Human
FOXP3 however has two major isoforms, a full length (FOXP3 FL isoform) and an alternatively spliced isoform
lacking exon 2 (FOXP3 ∆E2 isoform), while mouse Foxp3 gene only produce the FOXP3 FL isoform. The roles
of these two isoform in health and disease have not been clearly defined. In this grant we present evidence
that patients who only express the FOXP3 ΔE2 isoform due to mutations developed autoimmune diseases. We
generated mice with Foxp3 exon 2 deletion to study the functionality of FOXP3 ΔE2 isoform in vivo and
demonstrated that Foxp3 ΔE2 mice developed a systemic autoimmunity resembling systemic lupus
erythematosus (SLE). We further demonstrated that Tregs expressing only the Foxp3 ΔE2 isoform were
unstable, transdifferentiated to effector T helpers, and were sufficient to induce SLE-like disease when
transferred into Tcrb-/- mice. We hypothesize that FOXP3 ΔE2, one of the two major isoforms in humans, is a
risk factor for development and/or severity of SLE. We will test our hypothesis in the following specific aims. (1)
Define the role of Foxp3 ΔE2 Tregs on lupus onset and severity. We hypothesize that Foxp3 ΔE2 Tregs have a
different transcriptomic program from Foxp3 FL Tregs and render them to be lineage instability. Under lupus
inducing environment, Foxp3 ΔE2 Tregs lose lineage identity in the periphery and transdifferentiate into
autoreactive effector cells, resulting earlier onset and/or more severe disease even in the presence of Foxp3
FL Tregs. (2) Define the impact of FOXP3 ΔE2 isoform on human Treg phenotypes and disease course of
systemic lupus. We hypothesize that the ratio of FOXP3 isoform expression determines human Treg
phenotypes and correlates with disease course of systemic lupus. We will determine whether the FOXP3
ΔE2:FOXP3 FL ratio, the existence and frequency of Tregs expressing mainly FOXP3 ΔE2 isoform correlate
with disease state of SLE using flow cytometry and a specially designed method of single cell RNA-Seq. We
will further test whether cytokine milieu in SLE patients regulates FOXP3 pre-mRNA splicing thus shift the
isoform expression. The information learned from these studies will provide novel insights into the physiological
functions of the naturally existing human FOXP3 ΔE2 isoform and would pave the way to develop efficient
clinical protocols aimed at shifting FOXP3 isoform expression as therapeutic treatment of SLE as well as other
autoimmune diseases.

## Key facts

- **NIH application ID:** 10194961
- **Project number:** 1R21AI159804-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** BAOHUA ZHOU
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $237,750
- **Award type:** 1
- **Project period:** 2021-04-12 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10194961

## Citation

> US National Institutes of Health, RePORTER application 10194961, FOXP3 ΔE2 Isoform in Treg Function and Pathophysiology of Lupus (1R21AI159804-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10194961. Licensed CC0.

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