Summary: Researchers identified differences in isoforms that control Treg cells and how that affects the body’s immune system response.
Source: Indiana University
Researchers at Indiana University School of Medicine are learning more about how special regulatory T cells can impact the immune system’s response and how those cells could be manipulated for potential treatments for food allergies and autoimmune diseases.
In a study recently published in Science 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 body’s immune function.
“There is a particular gene that controls this regulatory group of T cells, which controls immune response,” said Baohua Zhou, PhD, lead author of the study and associate professor of pediatrics for IU 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 splicing—a 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?”
FOXP3 exon 2 controls Treg stability and autoimmunity
Differing from the mouse Foxp3 gene that encodes only one protein product, human FOXP3 encodes two major isoforms through alternative splicing—a longer isoform (FOXP3 FL) containing all the coding exons and a shorter isoform lacking the amino acids encoded by exon 2 (FOXP3 ΔE2).
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 with Foxp3 exon 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 ΔE2 are unstable and sufficient to induce autoimmunity when transferred into Tcrb-deficient mice.
Mechanistically, the FOXP3 ΔE2 isoform allows increased expression of selected cytokines, but decreased expression of a set of positive regulators of Foxp3 without 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 Treg stability and immune homeostasis.