Lymphatic endothelial transcription factor Tbx1 promotes an immunosuppressive microenvironment to facilitate post-myocardial infarction repair

Wenfeng Wang; Xiao Li; Xiaoning Ding; Shanshan Xiong; Zhenlei Hu; Xuan Lu; Kan Zhang; Heng Zhang; Qianwen Hu; Kaa Seng Lai; Zhongxiang Chen; Junjie Yang; Hejie Song; Ye Wang; Lu Wei; Zeyang Xia; Bin Zhou; Yulong He; Jun Pu; Xiao Liu; Rongqin Ke; Tao Wu; Chuanxin Huang; Antonio Baldini; Min Zhang; Zhen Zhang

doi:10.1016/j.immuni.2023.07.019

Lymphatic endothelial transcription factor Tbx1 promotes an immunosuppressive microenvironment to facilitate post-myocardial infarction repair

Immunity. 2023 Oct 10;56(10):2342-2357.e10. doi: 10.1016/j.immuni.2023.07.019. Epub 2023 Aug 24.

Authors

Wenfeng Wang¹, Xiao Li², Xiaoning Ding¹, Shanshan Xiong¹, Zhenlei Hu³, Xuan Lu⁴, Kan Zhang⁵, Heng Zhang⁶, Qianwen Hu⁶, Kaa Seng Lai¹, Zhongxiang Chen¹, Junjie Yang¹, Hejie Song¹, Ye Wang¹, Lu Wei¹, Zeyang Xia⁷, Bin Zhou⁸, Yulong He⁹, Jun Pu¹⁰, Xiao Liu¹¹, Rongqin Ke¹², Tao Wu¹³, Chuanxin Huang⁶, Antonio Baldini¹⁴, Min Zhang¹⁵, Zhen Zhang¹⁶

Affiliations

¹ Pediatric Translational Medicine Institute and Pediatric Congenital Heart Disease Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
² Gene Editing Laboratory, The Texas Heart Institute, Houston, TX 77030, USA.
³ Department of Cardiovascular Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
⁴ Silver Snake (Shanghai) Medical Science and Technique Co., Ltd., Shanghai 200030, China.
⁵ Department of Anesthesiology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
⁶ Shanghai Institute of Immunology and Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
⁷ Department of Neurosurgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
⁸ The State Key Laboratory of Cell Biology, CAS Center for Excellence on Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
⁹ Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China.
¹⁰ State Key Laboratory for Oncogenes and Related Genes, Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai 200127, China.
¹¹ BGI-Shenzhen, Shenzhen 518083, China.
¹² School of Medicine and School of Biomedical Sciences, Huaqiao University, Quanzhou, Fujian 362021, China.
¹³ Shanghai Collaborative Innovative Center of Intelligent Medical Device and Active Health, Shanghai University of Medicine & Health Sciences, Shanghai 201318, China.
¹⁴ Institute of Genetics and Biophysics "ABT," CNR, Naples 80131, Italy; Department of Molecular Medicine and Medical Biotechnologies, University of Naples, Federico II, Naples 80131, Italy.
¹⁵ Pediatric Translational Medicine Institute and Pediatric Congenital Heart Disease Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China. Electronic address: minzhang5099@gmail.com.
¹⁶ Pediatric Translational Medicine Institute and Pediatric Congenital Heart Disease Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China; Shanghai Collaborative Innovative Center of Intelligent Medical Device and Active Health, Shanghai University of Medicine & Health Sciences, Shanghai 201318, China. Electronic address: zhenzhang@sjtu.edu.cn.

PMID: 37625409
DOI: 10.1016/j.immuni.2023.07.019

Abstract

The heart is an autoimmune-prone organ. It is crucial for the heart to keep injury-induced autoimmunity in check to avoid autoimmune-mediated inflammatory disease. However, little is known about how injury-induced autoimmunity is constrained in hearts. Here, we reveal an unknown intramyocardial immunosuppressive program driven by Tbx1, a DiGeorge syndrome disease gene that encodes a T-box transcription factor (TF). We found induced profound lymphangiogenic and immunomodulatory gene expression changes in lymphatic endothelial cells (LECs) after myocardial infarction (MI). The activated LECs penetrated the infarcted area and functioned as intramyocardial immune hubs to increase the numbers of tolerogenic dendritic cells (tDCs) and regulatory T (Treg) cells through the chemokine Ccl21 and integrin Icam1, thereby inhibiting the expansion of autoreactive CD8⁺ T cells and promoting reparative macrophage expansion to facilitate post-MI repair. Mimicking its timing and implementation may be an additional approach to treating autoimmunity-mediated cardiac diseases.

Keywords: Tbx1; autoimmunity; cardiac repair; heart; immune suppression; lymphangiogenesis; lymphatic endothelial cells; myocardial infarction.