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Fox Chase Researchers Identify Key Molecular Circuit Regulating Gut Immune Function
PHILADELPHIA (September 8, 2021)—Researchers at Fox Chase Cancer Center have identified a molecular circuit that plays a key role in regulating gut immunity. The researchers say the discovery could be a first step in the development of new therapies for colitis, inflammatory bowel disease (IBD), and other disorders.
“Our gut harbors about 100 trillion microbes, and our immune system is responsible for preventing them from invading the body. In so doing, the immune system must maintain a careful balance between effective response to pathogens and a harmful overresponse. When this balance is perturbed it can lead to autoimmune disorders, including colitis and inflammatory bowel disease,” said Dietmar J. Kappes, PhD, a professor in the Blood Cell Development and Function program and director of the Transgenic Mouse Facility at Fox Chase.
In the study, Kappes and Jayati Basu, PhD, an assistant research professor in Kappes’ lab, showed for the first time how the transcription factor ThPOK creates an autoregulatory loop to stably maintain its own persistent expression to support immune function throughout the body.
Previous groundbreaking research by Kappes’ lab showed that ThPOK plays a critical role in the development of white blood cells called T cells by triggering progenitor cells to differentiate into mature immune “helper” cells called CD4 T cells. Interestingly, ThPOK remains continuously expressed in mature CD4 T cells, although less was known about its function in such mature cells.
Therefore, Kappes and Basu set out to answer how ThPOK expression is maintained in the context of mature CD4 cells and what happens to mature helper T cell function when ThPOK expression is prevented in these cells. They used a novel genetically engineered “knockout” mouse model to discover a genetic regulatory switch that maintains ThPOK expression in mature CD4 T cells.
When Kappes and Basu induced colitis in genetically altered mice in which this regulatory switch is turned off, the mice developed a much milder form of colitis, indicating that disrupting the ThPOK autoregulatory cycle offered them substantial protection from this disease. “It suggests that manipulating this circuit could be used in a therapeutic application,” Kappes said.
The researchers found that disruption of this switch caused the CD4 “helper” cells to stop functioning properly. Instead, they adopted features of a distinct T cell subtype known as colonic T reg cells, which regulate the autoimmune response in the gut. Upon entering the gut, these T reg cells in turn converted into another type of T cell called intraepithelial lymphocytes, or IEL, which protect the gut from infection.
Utilizing state-of-the-art modern molecular genomic tools, Kappes and Basu further revealed that this autoregulatory loop fundamentally controls the genome-wide regulatory landscape that “hardwires” helper T cell identity and function. “Even though this particular study focused on the gut and colitis, it could have applications to other cases of immune system dysfunction, including diabetes and HIV,” Kappes said.
“Targeting this molecular circuit with probiotics, prebiotics, and special diet will not only help IBD patients but will also protect cancer patients from harmful side effects of chemo and immunotherapy,” added Basu.
The paper, “Essential Role of a ThPOK Autoregulatory Loop in the Maintenance of Mature CD4 + T Cell Identity and Function,” was published in the journal Nature Immunology.
Fox Chase Cancer Center (Fox Chase), which includes the Institute for Cancer Research and the American Oncologic Hospital and is a part of Temple Health, is one of the leading comprehensive cancer centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase is also one of just 10 members of the Alliance of Dedicated Cancer Centers. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence five consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.
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