期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 125, 期 10, 页码 3952-3964出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI81227
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资金
- Association Francaise Contre les Myopathies
- Viral Vector Core of the CHU de Nantes
- INSERM [UMR 1089]
- Fondation Progreffe
- Societe Francophone de Transplantation
- National Research Agency via the investment of the future program [ANR-11-LABX-0016-01, ANR-10-IBHU-005]
- Institut Hospitalo-Universitaire-Centre Europeen des Sciences de la Transplantation et Immunotherapie project
- French Government
- Junior Basic Science grant from European Society for Organ Transplantation (ESOT)
- Roche Organ Transplantation Research Foundation (ROTRF) grant
- INSERM-Region Pays de la Loire Fellowship
- Fondation pour la Recherche Medicale
- Progreffe
Cytokines and metabolic pathway-controlling enzymes regulate immune responses and have potential as powerful tools to mediate immune tolerance. Blockade of the interaction between CD40 and CD40L induces long-term cardiac allograft survival in rats through a CD8(+)CD45RC(lo) Treg potentiation. Here, we have shown that the cytokine IL-34, the immunoregulatory properties of which have not been previously studied in transplantation or T cell biology, is expressed by rodent CD8(+)CD45RC(lo) Tregs and human FOXP3(+)CD45RC(lo)CD8(+) and CD4(+) Tregs. IL-34 was involved in the suppressive function of both CD8+ and CD4(+) Tregs and markedly inhibited alloreactive immune responses. Additionally, in a rat cardiac allograft model, IL-34 potently induced transplant tolerance that was associated with a total inhibition of alloantibody production. Treatment of rats with IL-34 promoted allograft tolerance that was mediated by induction of CD8(+) and CD4(+) Tregs. Moreover, these Tregs were capable of serial tolerance induction through modulation of macrophages that migrate early to the graft. Finally, we demonstrated that human macrophages cultured in the presence of IL-34 greatly expanded CD8(+) and CD4(+) FOXP3(+) Tregs, with a superior suppressive potential of antidonor immune responses compared with non-IL-34-expanded Tregs. In conclusion, we reveal that IL-34 serves as a suppressive Treg-specific cytokine and as a tolerogenic cytokine that efficiently inhibits alloreactive immune responses and mediates transplant tolerance.
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