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Donor Lymphocyte Infusion Induces Long-Term Donor-Specific Cardiac Xenograft Survival through Activation of Recipient Double-Negative Regulatory T Cells¹

Wenhao Chen^*, Dejun Zhou^*, Jose R. Torrealba^*, Thomas K. Waddell^*, David Grant^* and Li Zhang^2,*,

^* Department of Laboratory Medicine and Pathobiology, Multi Organ Transplantation Program, Toronto General Research Institute, University Health Network, and Department of Immunology, University of Toronto, Toronto, Ontario, Canada

Previous studies have shown that pretransplant donor lymphocyte infusion (DLI) can enhance xenograft survival. However, the mechanism by which DLI induces xenograft survival remains obscure. Using T cell subset-deficient mice as recipients we show that CD4⁺, but not CD8⁺, T cells are necessary to mediate the rejection of concordant cardiac xenografts. Adoptive transfer of naive CD4⁺ T cells induces rejection of accepted cardiac xenografts in CD4^–/– mice. This rejection can be prevented by pretransplant DLI in the absence of any other treatment. Furthermore, we demonstrate that DLI activates -TCR⁺CD3⁺CD4^–CD8^– double-negative (DN) regulatory T (Treg) cells in xenograft recipients, and that DLI-activated DN Treg cells can inhibit the proliferation of donor-specific xenoreactive CD4⁺ T cells in vitro. More importantly, adoptive transfer of DLI-activated DN Treg cells from xenograft recipients can suppress the proliferation of xenoreactive CD4⁺ T cells and their ability to produce IL-2 and IFN- in vivo. Adoptive transfer of DLI-activated DN Treg cells also prevents CD4⁺ T cell-mediated cardiac xenograft rejection in an Ag-specific fashion. These data provide direct evidence that DLI can activate recipient DN Treg cells, which can induce donor-specific long-term cardiac xenograft survival by suppressing the proliferation and function of donor-specific CD4⁺ T cells in vivo.

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