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¹ Department of Laboratory Medicine and Pathobiology and Department of Immunology, University of Toronto, Multi Organ Transplantation Program, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario M5G 2C4, Canada
² Department of Medical Biophysics and Immunology, University of Toronto, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2M9, Canada

Address correspondence to Li Zhang, Toronto General Hospital Research Institute, Department of Laboratory Medicine and Pathobiology, CCRW 2-809, 101 College Street, Toronto, Ontario M5G 2C4, Canada. Phone: 416-340-4915; Fax: 416-597-9749; E-mail: lzhang{at}transplantunit.org

Lymphoproliferative (lpr) mice, which lack functional Fas receptor expression and develop autoimmune lymphoproliferative disease, have an accumulation of T cell receptor-ß⁺CD4^-CD8^- (double negative T cells [DNTC]) in the periphery. The function of the accumulating DNTC is not clear. In this study we demonstrate that B6/lpr DNTC can dose dependently kill syngeneic CD8⁺ and CD4⁺ T cells from wild-type B6 mice through Fas/Fas ligand interactions in vitro. We also demonstrate that B6/lpr DNTC that are activated and expand in vivo are able to specifically down-regulate allogeneic immune responses mediated by syngeneic Fas⁺CD4⁺ and CD8⁺ T cells in vivo. B6/lpr DNTC that have been preactivated in vivo by infusion of either class I– (bm1) or class II– (bm12) mismatched allogeneic lymphocytes are able to specifically enhance the survival of bm1 or bm12, but not third-party skin allografts when adoptively transferred into naive B6^+/+ mice. These findings clearly demonstrate that B6/lpr DNTC have a potent immune regulatory function in vitro and in vivo. They also provide new insights into the mechanisms involved in the development of autoimmune disease in lpr mice.

Key Words: autoimmune • transplantation • immune tolerance • suppressor T lymphocytes • Fas ligand

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