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Open Access Rapamycin Generates Graft-Homing Murine Suppressor CD8+ T Cells That Confer Donor-Specific Graft Protection

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It has been reported that rapamycin (RPM) can induce de novo conversion of the conventional CD4+Foxp3 T cells into CD4+Foxp3+ regulatory T cells (iTregs) in transplantation setting. It is not clear whether RPM can similarly generate suppressor CD8+ T cells to facilitate graft acceptance. In this study, we investigated the ability of short-term RPM treatment in promoting long-term acceptance (LTA) of MHC-mismatched skin allografts by generating a CD8+ suppressor T-cell population. We found that CD4 knockout (KO) mice (in C57BL/6 background, H-2b) can promptly reject DBA/2 (H-2d) skin allografts with mean survival time (MST) being 13 days (p < 0.01). However, a short course RPM treatment in these animals induced LTA with graft MST longer than 100 days. Adoptive transfer of CD8+ T cells from LTA group into recombination-activating gene 1 (Rag-1)-deficient mice provided donor-specific protection of DBA/2 skin grafts against cotransferred conventional CD8+ T cells. Functionally active immunoregulatory CD8+ T cells also resided in donor skin allografts. Eighteen percent of CD8+ suppressor T cells expressed CD28 as measured by flow cytometry, and produced reduced levels of IFN-γ, IL-2, and IL-10 in comparison to CD8+ effector T cells as measured by ELISA. It is unlikely that CD8+ suppressor T cells mediated graft protection via IL-10, as IL-10/Fc fusion protein impaired RPM-induced LTA in CD4 KO mice. Our data supported the notion that RPM-induced suppressor CD8+ T cells home to the allograft and exert donor-specific graft protection.

Keywords: CD4 knockout; CD8+ T cells; Rapamycin; Rejection; Suppressor T cells; Transplantation

Document Type: Research Article


Affiliations: Department of Medicine, Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

Publication date: November 1, 2011

More about this publication?
  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.

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