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* Laboratory of Immunology, Cancer Research Institute and
Department of Pathology, Seoul National University College of Medicine, Seoul, Korea;
Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, Korea;
Graduate School of Life Sciences and Biotechnology, Korea University, Seoul, Korea;
¶ Department of Microbiology, Columbia University Medical Center, New York, NY 10032;
|| The Jackson Laboratory, Bar Harbor, ME 04609;
# Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea; and
** Xenotransplantation Research Center, Seoul National University Hospital, Seoul, Korea
The role of NKT cells during immune responses is diverse, ranging from antiviral and antitumor activity to the regulation of autoimmune diseases; however, the regulatory function of CD1d-dependent NKT cells in rejection responses against allogeneic graft is uncertain. In this study, we demonstrated the direct regulatory effects of CD1d-dependent NKT cells using an allogeneic skin transplantation model. H-Y-mismatched skin graft survival was shortened in CD1d–/– recipients compared with wild-type recipients. Adoptive transfer of syngeneic NKT cells via splenocytes or hepatic mononuclear cells into CD1d–/– recipients restored graft survival times to those of wild-type recipients. 
-Galactosylceramide, a specific activator of NKT cells, further prolonged graft survival. Although CD1d-dependent NKT cells did not extend skin graft survival in either major or complete minor histocompatibility-mismatched models, these cells affected graft survival in minor Ag mismatch models according to the magnitude of the antigenic difference. The afferent arm of NKT cell activation during transplantation required CD1d molecules expressed on host APCs and the migration of CD1d-dependent NKT cells into grafts. Moreover, the regulatory effects of CD1d-dependent NKT cells against alloantigen were primarily IL-10 dependent. Taken together, we concluded that CD1d-dependent NKT cells may directly affect the outcome of allogeneic skin graft through an IL-10-dependent regulatory mechanism.
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