1. Academic Validation
  2. USP25 deficiency promotes T cell dysfunction and transplant acceptance via mitochondrial dynamics

USP25 deficiency promotes T cell dysfunction and transplant acceptance via mitochondrial dynamics

  • Int Immunopharmacol. 2023 Feb 21;117:109917. doi: 10.1016/j.intimp.2023.109917.
Junbo Li 1 Jingzeng Wang 1 Tianhui Pan 1 Xi Zhou 1 Huifang Yang 1 Lu Wang 1 Guobin Huang 1 Chen Dai 1 Bo Yang 1 Bo Zhang 1 Yuanyuan Zhao 1 Peixiang Lan 2 Zhishui Chen 3
Affiliations

Affiliations

  • 1 Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 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.
  • 2 Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 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: lansong9783@126.com.
  • 3 Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 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: zschen@tjh.tjmu.edu.cn.
Abstract

Background: During organ transplantation, pharmacologic drugs targeting T cell activation signal to inhibit T cell-mediated allo-rejection are insufficient and not durable to suppress chronic rejection. Recent advances highlight an exhausted or dysfunctional status of T cells, which favor transplant acceptance.

Methods: The models of MHC-mismatched (BALB/c to C57BL/6 or USP25 KO mice) heterotopic heart transplantation and skin transplantation were utilized to evaluate the regulatory effects of Ubiquitin-Specific Protease 25(USP25) deficiency in vivo. The consequences of USP25 deficiency on murine T-cell proliferation, activation, cytokine secretion, mixed lymphocyte reaction (MLR) and energy metabolism were investigated in vitro. The signaling pathway of T cells in knock out mice was detected by Western blotting and Co-IP.

Results: We found T cells were dysfunctional inUSP25KO mice. Due to T cell dysfunction, skin and heart graft had a longer survival. In these dysfunctional T cells, mitochondria number and cristae condensation were decreased. Impaired mitochondrial mass and function favored to allo-graft acceptance. Furthermore, USP25 interacted with ATP5A and ATP5B to promote their stability.

Conclusions: Our data suggest that USP25 is a potential target to induce T cell dysfunction and allo-graft tolerance. And USP25 mediated mitochondrial homeostasis may contribute to reverse T cell exhaustion or dysfunction in tumor and chronic Infection.

Keywords

ATP5a1, ATP5b; Mitochondrial dynamics; USP25, T cell dysfunction.

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