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International Immunology Advance Access published online on January 13, 2006
International Immunology, doi:10.1093/intimm/dxh368
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© The Japanese Society for Immunology. 2006. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org
Received September 12, 2005
Accepted November 7, 2005

Article

Transfer of regulatory T cells generated ex vivo modifies graft rejection through induction of tolerogenic CD4+CD25+ cells in the recipient

Song Guo Zheng 1, Lingzhong Meng 1, Ju Hua Wang 1, Meguru Watanabe 2, Mark L. Barr 2, Donald V. Cramer 2, J. Dixon Gray 1, and David A. Horwitz 1 *

1 Division of Rheumatology and Immunology, Department of Medicine, 2011 Zonal Avenue, HMR 711, USA
2 Department of Cardiothoracic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA

* To whom correspondence should be addressed.
David A. Horwitz, E-mail: dhorwitz{at}usc.edu


  Abstract

Certain CD4+CD25+ T cells can induce and maintain T-cell non-responsiveness to donor alloantigens and have therapeutic potential in solid organ transplantation. Peripheral CD4+CD25- cells alloactivated with IL-2 and transforming growth factor {beta} (TGF-{beta}) ex vivo express the transcription factor FoxP3, and become potent antigen-specific CD4+CD25- suppressor cells. Here we report that the transfer of TGF-{beta}-induced regulatory CD4+ and CD8+ T cells (Tregs) co-incident with transplantation of a histoincompatible heart resulted in extended allograft survival. To account for this result, we injected non-transplanted mice with a single dose of CD4+ and CD8+ Tregs and transferred donor cells every 2 weeks to mimic the continuous stimulation of a transplant. We observed increased splenic CD4+CD25+ cells that were of recipient origin. These cells rendered the animals non-responsive to donor alloantigens by an antigen-specific and cytokine-dependent mechanism of action. Both the increased number of CD4+CD25+ cells and their tolerogenic effect were dependent on continued donor antigen boosting. Thus, Tregs generated ex vivo can act like a vaccine that generates host suppressor cells with the potential to protect MHC-mismatched organ grafts from rejection.

Keywords: cardiac allografts; TGF-{beta}; tolerance; transplantation; regulatory T cells.
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