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Both Infiltrating Regulatory T Cells and Insufficient Antigen Presentation Are Involved in Long-Term Cardiac Xenograft Survival¹

Wenhao Chen^*,, Jun Diao^*, Stanislaw M. Stepkowski and Li Zhang^2,*,,

^* Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto; Department of Immunology, University of Toronto, Toronto, Ontario, Canada; and Division of Immunology and Organ Transplantation, University of Texas Medical School at Houston, Houston, Texas 77030

We have previously shown that pretransplant donor lymphocyte infusion (DLI) together with transient depletion of CD4⁺ T cells could induce permanent rat-to-mouse heart graft survival, whereas depleting CD4⁺ T cells alone failed to do so. In this study, we investigated the mechanism leading to long-term xenograft survival. We found that peripheral CD4⁺ T cells from DLI/anti-CD4-treated mice could mount rat heart graft rejection after adoptive transfer into B6 CD4^–/– mice. Infusing donor-Ag-loaded mature dendritic cells (DCs) could break long-term cardiac xenograft survival in DLI/anti-CD4-treated mice. Interestingly, when the number and phenotype of graft-infiltrating cells were compared between anti-CD4- and DLI/anti-CD4-treated groups, we observed a significant increase in both the number and suppressive activity of -TCR⁺CD3⁺CD4^–CD8^– double negative regulatory T cells and decrease in the numbers of CD4⁺ and CD8⁺ T cells in the xenografts of DLI/anti-CD4-treated mice. Moreover, there was a significant reduction in MHC class II-high DCs within the xenografts of DLI/anti-CD4-treated recipients. DCs isolated from the xenografts of anti-CD4- but not DLI/anti-CD4-treated recipients could stimulate CD4⁺ T cell proliferation. Our data indicate that functional anti-donor T cells are present in the secondary lymphoid organs of the mice that permanently accepted cardiac xenografts. Their failure to reject xenografts is associated with an increase in double negative regulatory T cells as well as a reduction in Ag stimulation by DCs found within grafts. These findings suggest that local regulatory mechanisms need to be taken into account to control anti-xenograft T cell responses.

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 is supported by the Canadian Institutes of Health Research (to L.Z.). L.Z. is a Clinical Research Chair in Transplantation cosponsored by the Canadian Institutes of Health Research and Wyeth-Ayerst Canada.

² Address correspondence and reprint requests to Dr. Li Zhang, Toronto General Research Institute, TMDT 2-807, 101 College Street, Toronto, Ontario, Canada. E-mail address: lzhang{at}uhnres.utoronto.ca

³ Abbreviations used in this paper: Tregs, regulatory T cells; DN, double negative; DLI, donor lymphocyte infusion; GICs, graft-infiltrating cells; GI, graft-infiltrating; DCs, dendritic cells; MHC-II, MHC class II.