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

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

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

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 β (TGF-β) ex vivo express the transcription factor FoxP3, and become potent antigen-specific CD4+CD25- suppressor cells. Here we report that the transfer of TGF-β-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.

Original languageEnglish (US)
Pages (from-to)279-289
Number of pages11
JournalInternational immunology
Volume18
Issue number2
DOIs
StatePublished - Feb 2006

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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