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

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.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.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.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.
Mesh Terms:
Animals, Graft Rejection, Graft Survival, Heart Transplantation, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mitochondrial Dynamics, Organ Transplantation, T-Lymphocytes, Transplantation Tolerance
Int Immunopharmacol
Date: Apr. 01, 2023
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