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* Department of Surgery,
Department of Microbiology and Immunology, and
Department of Pathology, University of Western Ontario, London, Ontario, Canada;
Immunology and Transplantation, Lawson Health Research Institute, London, Ontario, Canada; and
¶ John P. Robarts Research Institute, London, Ontario, Canada
The ability to control the response of B cells is of particular interest in xenotransplantation as Ab-mediated hyperacute and acute xenograft rejection are major obstacles in achieving long-term graft survival. Regulatory T cells have been proven to play a very important role in the regulation of immune responses to self or non-self Ags. Previous studies have shown that TCR
β+CD3+CD4–CD8– (double-negative (DN)) T cells possess an immune regulatory function, capable of controlling antidonor T cell responses in allo- and xenotransplantation through Fas-Fas ligand interaction. In this study, we investigated the possibility that xenoreactive DNT cells suppress B cells. We found that DNT cells generated from wild-type C57BL/6 mice expressed B220 and CD25 after rat Ag stimulation. These xenoreactive B220+CD25+ DNT cells lysed activated, but not naive, B and T cells. This killing, which took place through cell-cell contact, required participation of adhesion molecules. Our results indicate that Fas ligand, TGF-β, TNF-, and TCR-MHC recognition was not involved in DNT cell-mediated syngenic cell killing, but instead this killing was mediated by perforin and granzymes. The xenoreactive DNT cells expressed high levels of granzymes in comparison to allo- or xenoreactive CD8+ T cells. Adoptive transfer of DNT cells in combination with early immune suppression by immunosuppressive analog of 15-deoxyspergualin, LF15-0195, significantly prolonged rat heart graft survival to 62.1 ± 13.9 days in mice recipients. In conclusion, this study suggests that xenoreactive DNT cells can control B and T cell responses in perforin/granzyme-dependent mechanisms. DNT cells may be valuable in controlling B and T cell responses in xenotransplantation.
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 study was supported by the Multi-Organ Transplant Program, the Lawson Health Research Institute at London Health Sciences Centre, and the Canada Institute for Health Research.
2 Address correspondence and reprint requests to Dr. Zhu-Xu Zhang, 339 Windermere Road, LHSC-C8-106, London, Ontario N6A 5A5, Canada. E-mail address: zhuxu.zhang{at}lhsc.on.ca
3 Abbreviations used in this paper: Treg, regulatory T; 7-AAD, 7-aminoactinomycin D; AVR, acute vascular rejection; DNT, CD3+CD4–CD8– double-negative T; FasL, Fas ligand.
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