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

Area of Science:

• Immunology
• Transplantation Biology
• Molecular Cell Biology

Background:

• Current immunosuppressants for organ transplantation inadequately prevent chronic rejection.
• T cell exhaustion or dysfunction is increasingly recognized as a factor promoting transplant acceptance.

Purpose of the Study:

• To investigate the role of ubiquitin-specific protease 25 (USP25) in T cell function and allo-graft acceptance.
• To explore USP25 as a potential therapeutic target for inducing transplant tolerance.

Main Methods:

• Utilized MHC-mismatched heart and skin transplantation models in USP25 knockout (USP25 KO) mice.
• Assessed T cell proliferation, activation, cytokine secretion, and energy metabolism in vitro.
• Analyzed T cell signaling pathways via Western blotting and Co-immunoprecipitation.

Main Results:

• USP25 deficiency led to T cell dysfunction, characterized by reduced mitochondrial mass and impaired function.
• USP25 KO mice exhibited prolonged survival of skin and heart grafts.
• USP25 was found to interact with ATP5A and ATP5B, influencing their stability.

Conclusions:

• USP25 deficiency induces T cell dysfunction, enhancing allo-graft acceptance.
• Targeting USP25 presents a potential strategy for inducing T cell dysfunction and promoting transplant tolerance.
• USP25-mediated mitochondrial homeostasis may be crucial for reversing T cell exhaustion in various conditions.