Donor‐Specific CD8+Foxp3+ T Cells Protect Skin Allografts and Facilitate Induction of Conventional CD4+Foxp3+ Regulatory T Cells |
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Authors: | T Kheradmand K L Pothoven Z J Zhang X Luo |
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Institution: | 1. Division of Nephrology and Hypertension, Department of Medicine, Northwestern University, Chicago, IL;2. Department of Allergy and Immunology, Northwestern University, Chicago, IL;3. Comprehensive Transplant Center, Northwestern University, Chicago, IL;4. Department of Microbiology‐Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL |
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Abstract: | CD4+ regulatory T cells play a critical role in tolerance induction in transplantation. CD8+ suppressor T cells have also been shown to control alloimmune responses in preclinical and clinical models. However, the exact nature of the CD8+ suppressor T cells, their induction and mechanism of function in allogeneic transplantation remain elusive. In this study, we show that functionally suppressive, alloantigen‐specific CD8+Foxp3+ T cells can be induced and significantly expanded by stimulating naïve CD8+ T cells with donor dendritic cells in the presence of IL‐2, TGF‐β1 and retinoic acid. These CD8+Foxp3+ T cells express enhanced levels of CTLA‐4, CCR4 and CD103, inhibit the up‐regulation of costimulatory molecules on dendritic cells, and suppress CD4 and CD8 T cell proliferation and cytokine production in a donor‐specific and contact‐dependent manner. Importantly, upon adoptive transfer, the induced CD8+Foxp3+ T cells protect full MHC‐mismatched skin allografts. In vivo, the CD8+Foxp3+ T cells preferentially traffic to the graft draining lymph node where they induce conventional CD4+Foxp3+ T cells and concurrently suppress effector T cell expansion. We conclude that donor‐specific CD8+Foxp3+ suppressor T cells can be induced and exploited as an effective form of cell therapy for graft protection in transplantation. |
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Keywords: | Allogeneic skin transplantation CD8 suppressor cells Cytotoxic T lymphocytes CD8α +CD11c+ dendritic cells CD4 regulatory T cells graft rejection transforming growth factor‐β 1 |
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