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Prepublished online as a Blood First Edition Paper on July 12, 2002; DOI 10.1182/blood-2002-01-0235.
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Blood, 1 November 2002, Vol. 100, No. 9, pp. 3408-3414
TRANSPLANTATION
Donor-lymphocyte infusion induces transplantation tolerance by
activating systemic and graft-infiltrating double-negative regulatory
T cells
Kevin J. Young,
Liming Yang,
M. James Phillips, and
Li Zhang
From the Departments of Laboratory Medicine and
Pathobiology and Immunology, Multi Organ Transplantation Program,
Toronto General Research Institute, University Health Network,
University of Toronto, ON, Canada.
Donor-lymphocyte infusion (DLI) before transplantation can lead to
specific tolerance to allografts in mice, nonhuman primates, and
humans. We and others have demonstrated a role for regulatory T
cells in DLI-induced, donor-specific transplantation tolerance, but it
is not known how regulatory T cells are activated and where they
execute their function. In this study, we observed, in both transgenic
and normal mice, that DLI before transplantation is required for
activation of   -T-cell-receptor-positive,
CD3+CD4 CD8 double-negative (DN)
regulatory T cells in the periphery of recipient mice. More
interestingly, DLI induced DN regulatory T cells to migrate
preferentially to donor-specific allogeneic skin grafts and to form a
majority of graft-infiltrating T cells in accepted skin allografts.
Furthermore, both recipient-derived peripheral and graft-infiltrating
DN T cells were able to suppress and kill antidonor CD8+ T
cells in an antigen-specific manner. These data indicate that DLI may
induce donor-specific transplantation tolerance by activating recipient
DN regulatory T cells in the periphery and by promoting migration of
regulatory T cells to donor-specific allogeneic skin grafts. Our
results also show that DN regulatory T cells can eliminate antidonor T
cells both systemically and locally, a finding suggesting that
graft-infiltrating T cells can be beneficial to graft survival.
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