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In Vitro and In Vivo Assessment of T, B and Myeloid Cells Suppressive Activity and Humoral Responses from Transplant Recipients
Published on: August 12, 2017
Inhibition of T cell polyamine metabolism promotes transplant acceptance by modulating cytotoxic CD8+ T cell
Renjie Tang1, Yuan Chang1, Yuqi An2
1Department of Cardiac Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China; Beijing Key Laboratory for Xenotransplantation, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
Insights
Polyamines regulate T-cell metabolism, crucial for preventing acute rejection (AR) in heart transplants. Inhibiting this pathway in T cells stops AR and improves graft survival, offering a new therapeutic target.
Area of Science:
- Immunology
- Molecular Biology
- Transplantation Science
Background:
- Polyamines, like spermidine, offer cardiovascular, antitumor, and longevity benefits.
- The role of T-cell polyamine metabolism in heart transplant acceptance is largely unknown.
Purpose of the Study:
- To investigate the role of T-cell polyamine metabolism in heart transplant acute rejection (AR).
- To explore polyamine metabolism as a potential therapeutic target for preventing AR.
Main Methods:
- Integrated preclinical (murine allografts) and clinical (human AR samples) studies.
- Conditional inhibition of T-cell polyamine metabolism.
- Analysis of cytotoxic CD8+ T cell differentiation and eIF5A hypusination.
Main Results:
- Polyamine metabolism was significantly upregulated in T cells during AR in both mice and humans.
- Inhibiting T-cell polyamine metabolism prevented AR and promoted long-term graft survival.
- Polyamine metabolism is essential for cytotoxic CD8+ T cell differentiation, mediated by eIF5A hypusination.
Conclusions:
- T-cell polyamine metabolism critically regulates cytotoxic CD8+ T cell differentiation and heart transplant AR.
- Targeting T-cell polyamine metabolism is a promising strategy for preventing AR and enhancing graft survival.
Abstract:
Polyamines, particularly spermidine, are well-documented for their cardiovascular protective, antitumor, and longevity-promoting properties. However, their role in heart transplantation, and specifically the contribution of T cell polyamine metabolism to transplant acceptance, remains undefined. In this study, we integrated preclinical and clinical studies to address this gap. We found that polyamine metabolism was significantly upregulated in T cells during acute rejection (AR) in both murine allografts and human AR samples. Critically, conditional inhibition of polyamine metabolism in T cells completely prevents AR and promotes long-term graft survival. Mechanistically, we found that polyamine metabolism is crucial for the differentiation of cytotoxic CD8+ T cells. Further, this regulatory effect was mediated by polyamine-dependent hypusination of eukaryotic initiation factor 5A (eIF5A), with inhibition of T cell eIF5A hypusination recapitulating the anti-AR effects of polyamine blockade. Our study identified T cell polyamine metabolism as a critical regulator of cytotoxic CD8+ T cell differentiation and AR in heart transplantation. Targeting this pathway holds promise as a novel therapeutic strategy for treating AR.
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