MTHFD2 ablation in T cells protects against heart transplant rejection by perturbing IRF4/PD-1 pathway through the metabolic-epigenetic nexus

Yuan Li; Zhang Chen; Jikai Cui; Jizhang Yu; Yuqing Niu; Shuan Ran; Song Wang; Weicong Ye; Heng Xu; Xi Zhang; Jie Wu; Jiahong Xia

doi:10.1016/j.healun.2023.07.009

MTHFD2 ablation in T cells protects against heart transplant rejection by perturbing IRF4/PD-1 pathway through the metabolic-epigenetic nexus

J Heart Lung Transplant. 2023 Nov;42(11):1608-1620. doi: 10.1016/j.healun.2023.07.009. Epub 2023 Jul 24.

Authors

Yuan Li¹, Zhang Chen¹, Jikai Cui¹, Jizhang Yu¹, Yuqing Niu¹, Shuan Ran¹, Song Wang¹, Weicong Ye², Heng Xu¹, Xi Zhang³, Jie Wu⁴, Jiahong Xia⁵

Affiliations

¹ Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
³ Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: zhangxi798@sina.com.
⁴ Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China. Electronic address: wujie426@hust.edu.cn.
⁵ Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China. Electronic address: jiahong.xia@mail.hust.edu.cn.

PMID: 37495036
DOI: 10.1016/j.healun.2023.07.009

Abstract

Background: One-carbon metabolism supports the activation, proliferation, and function of multiple immune cells. However, researchers have not clearly determined whether and how one-carbon metabolic enzymes contribute to heart transplant rejection.

Methods: We investigated the dynamic metabolic adaptation in grafts during heart transplant rejection by conducting transcriptomics, metabolomics and single-cell RNA sequencing studies of cardiac tissue from human and mouse heart transplant recipients. We also assessed the expression of the one-carbon metabolic enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in cardiac grafts by immunofluorescence and flow cytometry assays. Then we constructed a murine heart transplant model with T cell-specific Mthfd2 knockout mice, analyzed T cells function by flow cytometry assays and enzyme-linked immunospot assays, and studied the mechanism by Cleavage Under Targets and Tagmentation assays. Finally, we studied the effect of a pharmacological inhibitor of MTHFD2 in humanized skin transplant model.

Results: We revealed that the one-carbon metabolism enzyme MTHFD2 was a hallmark of alloreactive T cells and was linked to T cell proliferation and function after exposure to alloantigen. And, Mthfd2 ablation prevented murine heart transplant rejection. Mechanistically, we found Mthfd2 ablation affected the interferon regulatory factor 4/programmed death-1 pathway through a metabolic-epigenetic mechanism involving H3K4me3. Furthermore, we found that inhibiting MTHFD2 attenuated human allograft rejection in a humanized skin transplant model.

Conclusions: These data show that the one-carbon metabolic enzyme MTHFD2 serves as a metabolic checkpoint of alloreactive T cells and suggest that it may be a potential therapeutic target for heart transplant rejection.

Keywords: IRF4; MTHFD2; T cells; heart transplant rejection; one-carbon metabolism.