This study was presented in part at the American Transplant Congress 2004, May 15–19, Boston, MA, the XX International Congress of the Transplantation Society, 5–10 September 2004, Vienna, Austria and at the World Transplant Congress 2006, July 22–27, Boston, MA.
New Insights into Mechanisms of Spontaneous Liver Transplant Tolerance: The Role of Foxp3-Expressing CD25+CD4+ Regulatory T Cells
Article first published online: 28 JUN 2008
© 2008 The Authors Journal compilation © 2008 The American Society of Transplantation and the American Society of Transplant Surgeons
American Journal of Transplantation
Volume 8, Issue 8, pages 1639–1651, August 2008
How to Cite
Li, W., Kuhr, C. S., Zheng, X. X., Carper, K., Thomson, A. W., Reyes, J. D. and Perkins, J. D. (2008), New Insights into Mechanisms of Spontaneous Liver Transplant Tolerance: The Role of Foxp3-Expressing CD25+CD4+ Regulatory T Cells. American Journal of Transplantation, 8: 1639–1651. doi: 10.1111/j.1600-6143.2008.02300.x
- Issue published online: 23 JUL 2008
- Article first published online: 28 JUN 2008
- Received 26 December 2007, revised 24 April 2008 and accepted for publication 28 April 2008
Liver allografts in mice are accepted across MHC barriers without requirement for immunosuppressive therapy. The mechanisms underlying this phenomenon remain largely undefined. In this study, we investigated the role of Foxp3-expressing CD25+CD4+ regulatory T cells (Treg) in the induction of murine liver transplant tolerance. Foxp3+CD25+CD4+ T cells were increased in liver grafts and recipient spleens from day 5 to day 100 posttransplantation, associated with enhanced CTLA4 and TGF-β expression and IL-4 production. Depletion of recipient CD25+CD4+ T cells using anti-CD25 mAb (250 μg/day) induced acute liver allograft rejection. This was associated with a decreased ratio of Foxp3+ Treg: T effector cells, decreased IL-4 and elevated IL-10 and IL-2 production by graft-infiltrating T cells, and reduced apoptotic activity of graft-infiltrating CD4+ and CD8+ T cells in anti-CD25-mAb-treated recipients. Thus, the data suggest that Foxp3+CD25+CD4+Treg are involved in spontaneous acceptance of liver allografts in mice. The ratio of Treg to T effector cells appears to determine liver transplant outcome. CTLA4, IL-4, TGF-β and apoptosis of graft-infiltrating T cells are also associated with liver transplant tolerance and may contribute, at least in part, to the mechanisms of Treg-mediated immune regulation in this model.