Allograft rejection mediated by memory T cells is resistant to regulation

*Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
^‡Transplantation Research Immunology Group, Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom; and
^§Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital, Harvard Medical School, Boston, MA 02115

Edited by Laurie H. Glimcher, Harvard Medical School, Boston, MA, and approved October 15, 2007 (received for review May 10, 2007)

Abstract

Alloreactive memory T cells may be refractory to many of the tolerance-inducing strategies that are effective against naive T cells and thus present a significant barrier to long-term allograft survival. Because CD4⁺CD25⁺ regulatory T cells (Tregs) are critical elements of many approaches to successful induction/maintenance of transplantation tolerance, we used MHC class I and II alloreactive TCR-transgenic models to explore the ability of antigen-specific Tregs to control antigen-specific memory T cell responses. Upon coadoptive transfer into RAG-1^−/− mice, we found that Tregs effectively suppressed the ability of naive T cells to reject skin grafts, but neither antigen-unprimed nor antigen-primed Tregs suppressed rejection by memory T cells. Interestingly, different mechanisms appeared to be active in the ability of Tregs to control naive T cell-mediated graft rejection in the class II versus class I alloreactive models. In the former case, we observed decreased early expansion of effector cells in lymphoid tissue. In contrast, in the class I model, an effect of Tregs on early proliferation and expansion was not observed. However, at a late time point, significant differences in cell numbers were seen, suggesting effects on responding T cell survival. Overall, these data indicate that the relative resistance of both CD4⁺ and CD8⁺ alloreactive memory T cells to regulation may mediate resistance to tolerance induction seen in hosts with preexisting alloantigen-specific immunity and further indicate the multiplicity of mechanisms by which Tregs may control alloimmune responses in vivo.

Footnotes

^¶To whom correspondence should be addressed. E-mail: turka{at}mail.med.upenn.edu
Author contributions: L.A.T. and N.D.J. are co-senior authors; J.Y. and M.O.B. contributed equally to this work; J.Y., M.O.B., M.C.-G., M.H.S., K.J.W., L.A.T., and N.D.J. designed research; J.Y., M.O.B., M.C.-G., J.Z., and H.E.R. performed research; J.Y., M.O.B., M.C.-G., M.H.S., K.J.W., L.A.T., and N.D.J. analyzed data; and J.Y., K.J.W., L.A.T., and N.D.J. wrote the paper.
↵ ^†Present address: Department of Internal Medicine, Gachon University of Medicine and Science, Incheon, South Korea.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.