Researchers may have found key to deprogram cells that lead to transplant rejection

HOUSTON-(Mar. 14, 2024) – Houston Methodist researchers identified a troublesome subset of T-cells in transplant recipients that may be a more effective therapeutic target for preventing transplant rejection in patients.

Each day, 17 people die waiting for organ transplants, but getting a new organ doesn’t guarantee survival. Despite immunosuppressive medications, rejection of transplanted organs happens in up to 50% of patients, depending on the type of organ transplanted and the duration since the transplantation.

Wenhao Chen, Ph.D., associate professor of transplant immunology with the Houston Methodist Research Institute, and his team used single-cell RNA sequencing to analyze the CD4+ T-cell response in transplantation scenarios and identified a subset that he referred to as “troublemakers.” They also discovered the mechanism behind what directs that T-cell response in animal transplant models.

This troublesome subset of CD4+ T-cells they discovered acts like stem cells and continuously generates functionally mature effector T-cells that attack transplanted organs. They also found that the transcription factor IRF4 is required for T-cells in that subset to become those organ-attacking effector T-cells. Thus, Chen says IRF4 is what needs to be targeted to solve the problem of transplant rejection or to develop an autoimmunity cure.

“T-cells play a central role in fighting infections and cancer, but they are also the key players in mediating autoimmune diseases and transplant rejection,” Chen said. “Our study demonstrated that IRF4 is a master regulator of T-cell function; a discovery that will allow development of innovative therapies for patients with chronic infections, cancers, autoimmune diseases and transplanted organs.”

Eliminating undesired CD4+ T-cell responses that could potentially lead to the loss of transplanted organs could eventually apply to all transplant patients, he said of this discovery.

“How to therapeutically inhibit IRF4 is the Nobel-prize winning question,” Chen said in reference to a past research study on this challenge. “If we can find a way to inhibit IRF4 as desired in activated T-cells, then I think most autoimmune diseases and transplant rejection will be solved.”

Their findings are described in an article titled “CD4+ T cell immunity is dependent on an intrinsic stem-like program” in a recent issue of Nature Immunology, a multidisciplinary journal that publishes papers with insight into the workings of the immune system.

“This revelation about the true troublemaker within the CD4+ T-cell population is just the tip of the iceberg,” Chen said. “I sincerely hope our findings garner widespread attention, motivating both researchers and patients to recognize the significance of targeting these troublemakers.”

Researchers collaborating with Chen on this multidisciplinary effort from the Immunobiology & Transplant Science Center at the Houston Methodist Research Institute include Dawei Zou, Guohua Wang, Yang Guo, Xiang Xiao, Xiaolong Zhang, Nancy M. Gonzalez, Laurie J. Minze and Xian C. Li; Zheng Yin, Lin Wang and Stephen T.C. Wong from the Systems Medicine and Bioengineering Department with the Houston Methodist Neal Cancer Center; Stephanie G. Yi, A. Osama Gaber and Rafik M. Ghobrial from the Department of Surgery in the J. C. Walter Jr. Transplant Center at Houston Methodist Hospital; and Shuang Li from the Center for Neuroregeneration at the Houston Methodist Research Institute.

The study was supported by internal funding from Houston Methodist Research Institute and U.S. National Institutes of Health (grants R01 AI132492 and R01 AI129906).

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For more information: CD4+ T-cell immunity is dependent on an intrinsic stem-like program. Nature Immunology DOI: https://doi.org/10.1038/s41590-023-01682-z (Jan. 2, 2024) Dawei Zou, Zheng Yin, Stephanie G. Yi, Guohua Wang, Yang Guo, Xiang Xiao, Shuang Li, Xiaolong Zhang, Nancy M. Gonzalez, Laurie J. Minze, Lin Wang, Stephen T.C. Wong, A. Osama Gaber, Rafik M. Ghobrial, Xian C. Li and Wenhao Chen.

Editorial Note: This news release was sourced from a story by Houston Methodist science writer Heather Lander, Ph.D.

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