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Location and Time-Dependent Control of Rejection by Regulatory T Cells Culminates in a Failure to Generate Memory T Cells¹

Manuela Carvalho-Gaspar^2,*, Nick D. Jones^2,3,*, Shiqiao Luo^*, Laurent Martin, Matthew O. Brook^* and Kathryn J. Wood^*

^* Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; and Service d’Anatomie Pathologique, Unité Propre de la Recherche et de L’ Enseignement Superieur 563/Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 645, Faculté de Médecine, Universite de Bourgogne, Dijon, France

Adaptive CD25⁺CD4⁺ regulatory T cells (Treg) can be induced following exposure to alloantigen and may function alongside naturally occurring Treg to suppress allograft rejection when present in sufficient numbers. However, the location of the Treg as they function in vivo and the mechanisms used to control donor-reactive T cells remains ill-defined. In this study, we used a CD8⁺ TCR transgenic model of skin allograft rejection to characterize in vivo activity of donor-reactive Treg cells during induction of transplantation tolerance. We demonstrate that, initially after skin transplantation, Treg attenuate the priming of donor-reactive naive CD8⁺ T cells in the lymphoid tissue draining the graft site. However, with time, peripheral suppression is overcome despite the continued presence of Treg, resulting in the priming of donor-reactive CD8⁺ T cells and graft infiltration by the resultant effector T cells and induction of a "Tc1-like" intragraft gene expression profile. These intragraft effector CD8⁺ T cells are then prevented from eliciting rejection by Treg that simultaneously infiltrate the skin allografts, resulting in a failure to generate donor-reactive memory CD8⁺ T cells. Overall, these data demonstrate for the first time that donor-reactive Treg can suppress allograft rejection using distinct mechanisms at different sites in vivo with the overall outcome of preventing the generation of donor-reactive memory T cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by was supported by Fundação para a Ciência e Tecnologia, Portugal (scholarship Praxis XXI/BD/18478/98, to M.C.-G.). N.D.J. is a Kidney Research U.K. Senior Research Fellow. K.J.W. holds a Royal Society Wolfson Research Merit award.

² M.C.-G. and N.D.J. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Nick D. Jones, Transplantation Research Immunology Group, Nuffield Department of Surgery, John Radcliffe Hospital, Oxford OX3 9DU, U.K. E-mail address: nicholas.jones{at}nds.ox.ac.uk

⁴ Abbreviations used in this paper: Treg, regulatory T cell; MLN, mesenteric lymph node; dLN, draining axillary lymph node; cLN, contralateral axillary lymph node; HPRT, hypoxanthine phosphoribosyl transferase.