Submitted May 25, 2006
Accepted August 26, 2006
In vitro expanded donor alloantigen-specific CD4+CD25+ regulatory T cells promote experimental transplantation tolerance
Dela Golshayan, Shuiping Jiang, Julia Tsang, Marina I Garin, Christian Mottet, and Robert I Lechler*
Department of Immunology, Imperial College, Hammersmith Hospital, London, UK
Department of Nephrology and Transplantation, King's College London School of Medicine, London, UK
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
* Corresponding author; email: robert.lechler{at}kcl.ac.uk.
CD4+CD25+ T cells (Tregs) play a critical role in the induction and maintenance of peripheral immune tolerance. In experimental transplantation models where tolerance was induced, donor-specific Tregs could be identified that were capable of transferring the tolerant state to naive animals. Furthermore, these cells appeared to have indirect allospecificity for donor antigens. Here we show that in vivo alloresponses can be regulated by donor alloantigen-specific Tregs selected and expanded in vitro. Using autologous dendritic cells pulsed with an allopeptide from H2-Kb we generated and expanded T cell lines from purified Tregs of CBA mice (H2k). Compared to fresh Tregs, the cell lines maintained their characteristic phenotype, suppressive function and homing capacities in vivo. When cotransferred with naive CD4+CD25- effector T cells into thymectomised and T cell-depleted CBA mice grafted with a CBK (H2k+Kb) skin, the expanded Tregs preferentially accumulated in the graft draining lymph nodes and within the graft while preventing CBK but not third party B10.A (H2k+Dd) skin graft rejection. In wild-type CBA these donor-specific Tregs significantly delayed CBK skin graft rejection without any other immunosuppression. Taken together these data suggest that in vitro generated tailored Tregs could be considered as a therapeutic tool to promote donor-specific transplantation tolerance.
