Summary: Researchers identified differences in isoforms that control Treg cells and how that affects the bodys immune system response.

Source: Indiana University

Researchers atIndiana University School of Medicineare learning more about how special regulatory T cells can impact the immune systems response and how those cells could be manipulated for potential treatments for food allergies and autoimmune diseases.

Ina study recently published inScience Immunology,researchers focused on regulatory T cells, or Treg cells, that regulate immune responses in the body and keep the immune system in order while fighting pathogens.

In some cases, the immune system becomes overly responsive, leading to autoimmune diseases, such as Type 1 diabetes or lupus, food allergies or other issues. Researchers were able to identify the differences in isoforms that control Treg cells and how that affects the bodys immune function.

There is a particular gene that controls this regulatory group of T cells, which controls immune response, saidBaohua Zhou, PhD, lead author of the study and associate professor of pediatrics forIU School of Medicine Department of Pediatrics.

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

The human gene FOXP3 produces two major isoforms through alternative splicinga longer isoform and a shorter isoform.

The two isoforms are naturally expressed in humans, but their differences in controlling regulatory T cell phenotype and functionality has been unclear. In this study, researchers showed patients expressing only the shorter isoform fail to maintain self-tolerance and develop issues like immunodeficiency, polyendocrinopathy and enteropathy X-linked (IPEX) syndrome.

They uncovered different 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 to change them, which could lead to new treatments for autoimmune diseases and allergies, Zhou said.

We could also potentially manipulate them to keep the body from responding improperly to diseases like cancer. If T reg cells are suppressing the antitumor response, can we change that?

Author: Christina GriffithsSource: Indiana UniversityContact: Christina Griffiths Indiana UniversityImage: The image is in the public domain

Original Research: Closed access.FOXP3 exon 2 controls Treg stability and autoimmunity by Baohua Zhou et al. Science Immunology

Abstract

FOXP3 exon 2 controls Treg stability and autoimmunity

Differing from the mouseFoxp3gene that encodes only one protein product, humanFOXP3encodes two major isoforms through alternative splicinga longer isoform (FOXP3 FL) containing all the coding exons and a shorter isoform lacking the amino acids encoded by exon 2 (FOXP3 E2).

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

In this study, we show that patients expressing only the shorter isoform fail to maintain self-tolerance and develop immunodeficiency, polyendocrinopathy, and enteropathy X-linked (IPEX) syndrome.

Mice withFoxp3exon 2 deletion have excessive follicular helper T (TFH) and germinal center B (GC B) cell responses, and develop systemic autoimmune disease with anti-dsDNA and antinuclear autoantibody production, as well as immune complex glomerulonephritis. Despite having normal suppressive function in in vitro assays, regulatory T cells expressing FOXP3 E2 are unstable and sufficient to induce autoimmunity when transferred intoTcrb-deficient mice.

Mechanistically, the FOXP3 E2 isoform allows increased expression of selected cytokines, but decreased expression of a set of positive regulators ofFoxp3without altered binding to these gene loci.

These findings uncover indispensable functions of the FOXP3 exon 2 region, highlighting a role in regulating a transcriptional program that maintains Tregstability and immune homeostasis.

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