2. Academic Validation
  3. Electrostimulation suppresses allograft rejection via promoting lymphatic regulatory T cell migration mediated by lymphotoxin - lymphotoxin receptor β signaling

Electrostimulation suppresses allograft rejection via promoting lymphatic regulatory T cell migration mediated by lymphotoxin - lymphotoxin receptor β signaling

  • Am J Transplant. 2024 Jul 9:S1600-6135(24)00392-7. doi: 10.1016/j.ajt.2024.06.019.
Huazhen Liu 1,  Helong Dai 2,  Feifei Qiu 3,  Yuchao Chen 4,  Chun-Ling Liang 4,  Bin Yang 5,  Nianqiao Gong 6,  Jonathan S Bromberg 7,  Zhenhua Dai 8
Affiliations

Affiliations

  • 1 Section of Immunology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; State Key Laboratory of Traditional Chinese Medicine Syndrome, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
  • 2 Department of Kidney Transplantation, Center of Organ Transplantation, the Second Xiangya Hospital of Central South University, Changsha, China.
  • 3 Section of Immunology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
  • 4 Section of Immunology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
  • 5 Department of Cardiovascular Sciences, College of Life Sciences University of Leicester, Leicester, UK.
  • 6 Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei, China. Electronic address: nqgong@tjh.tjmu.edu.cn.
  • 7 Kidney and Pancreas Transplantation, Department of Surgery and Department of Microbiology & Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA. Electronic address: jbromberg@som.umaryland.edu.
  • 8 Section of Immunology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China. Electronic address: daizhenhua@gzucm.edu.cn.
PMID: 38992495 DOI: 10.1016/j.ajt.2024.06.019
Abstract

Conventional immunosuppressants that suppress allograft rejection cause various side effects. Although regulatory T cells (Tregs) are essential for allograft survival, the limited efficacy of Treg therapy demands improvement. Thus, it is imperative to seek new approaches to enhancing Treg suppression. Low-intensity electrostimulation (ES) has been shown to exert antiinflammatory effects without causing major adverse reactions. However, it remains unknown whether and how ES regulates alloimmunity. Here, we found that regional ES delayed murine skin allograft rejection and promoted long-term allograft survival induced by an mTOR Inhibitor, rapamycin. ES also extended islet allograft survival. Mechanistically, ES enhanced the expression of lymphotoxin α (LTα) on Tregs after transplantation. Blockade of lymphotoxin β receptor-mediated nonclassical NFκB signaling suppressed lymphatic Treg migration and largely reversed the effects of ES on allograft survival. Moreover, ES failed to extend allograft survival when recipients lacked LTα/lymph nodes or if transferred Tregs lacked LTα. Therefore, ES promoted the lymphatic migration of CD4+Foxp3+ Tregs by upregulating their surface expression of LTα. Finally, ES augmented expression of LTα on murine or human Tregs, but not conventional T cells, while promoting their calcium influx in vitro. This ES-mediated upregulation of LTα relied on calcium influx. Thus, our findings have unveiled novel mechanisms underlying ES-mediated immunoregulation.

Keywords

Treg; electrostimulation; lymphotoxin; nonclassical NFκB; transplantation.

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