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Important factors for regulating the body’s immune response

Overview: Researchers identified differences in isoforms that control Treg cells and how that affects the response of the body’s immune system.

Source: University of Indiana

Researchers at Indiana University School of Medicine are learning more about how special regulatory T cells can influence the immune system’s response and how those cells can be manipulated for potential treatments for food allergies and autoimmune diseases.

In a recently published study in Science Immunology, researchers focused on regulatory T cells, or Treg cells, which regulate immune responses in the body and keep the immune system in order while fighting pathogens.

In some cases, the immune system overreacts, leading to autoimmune diseases, such as type 1 diabetes or lupus, food allergies, or other problems. Researchers were able to identify the differences in isoforms that control Treg cells and how that affects the body’s immune function.

“There is a particular gene that controls this regulatory group of T cells, which regulates the immune response,” said Baohua Zhou, PhD, lead author of the study and associate professor of pediatrics for the IU School of Medicine Department of Pediatrics.

“Treg cells can help maintain the right balance to help the immune system not react too strongly or too weakly.”

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The human FOXP3 gene produces two major isoforms by alternative splicing: a longer isoform and a shorter isoform. Image is in the public domain

The human FOXP3 gene produces two major isoforms by alternative splicing: a longer isoform and a shorter isoform.

The two isoforms are naturally expressed in humans, but their differences in regulating the regulatory T cell phenotype and functionality are unclear. In this study, researchers showed that patients expressing only the shorter isoform do not maintain self-tolerance and develop problems such as immunodeficiency, polyendocrinopathy, and enteropathy X-linked (IPEX) syndrome.

They discovered several functions of the FOXP3 isoforms to regulate Treg cells and immune homeostasis.

“Now that we know the different functions of the isoforms, we hope to study how we can alter them, which could lead to new treatments for autoimmune diseases and allergies,” Zhou said.

“We could also potentially manipulate them to prevent the body from responding incorrectly to diseases like cancer. If Treg cells suppress the anti-tumor response, can we change that?”

About this research news about the immune system

Author: Christina Griffiths
Source: University of Indiana
Contact: Christina Griffiths – Indiana University
Image: The image is in the public domain

Original research: Closed access.
FOXP3 exon 2 regulates Treg stability and autoimmunityby Baohua Zhou et al. Science Immunology


Abstract

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FOXP3 exon 2 regulates Treg stability and autoimmunity

Different from the mouse Foxp3 gene that codes for only one protein product, human FOXP3 encodes two major isoforms via alternative splicing: a longer isoform (FOXP3 FL) containing all coding exons and a shorter isoform lacking the amino acids encoded by exon 2 (FOXP3 ΔE2).

The two isoforms are naturally expressed in humans, but their differences in regulating the regulatory T cell phenotype and functionality remain unclear.

In this study, we show that patients expressing only the shorter isoform do not maintain self-tolerance and develop immunodeficiency, polyendocrinopathy and enteropathy X-linked (IPEX) syndrome.

Mice with Foxp3 exon 2 deletion have excessive follicular helper T (TFH) and germinal center B (GC B) cell responses, and developing systemic autoimmune disease with anti-dsDNA and antinuclear autoantibody production, as well as immune complex glomerulonephritis. Despite having a normal suppressive function in in vitro assays, regulatory T cells expressing FOXP3 ΔE2 are unstable and sufficient to induce autoimmunity when transferred to Tcrb-deficient mice.

Mechanistically, the FOXP3 ΔE2 isoform allows increased expression of selected cytokines, but decreased expression of a range of positive regulators of Foxp3 without altered binding to these gene loci.

These findings reveal indispensable functions of the FOXP3 exon 2 region, highlighting a role in regulating a transcription program that Treg stability and immune homeostasis.

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