title: Tolerogenic interactions between CD8+dendritic cells and NKT cells prevent rejection of bone marrow and organ grafts.
abstract: The combination of total lymphoid irradiation and anti-T-cell antibodies safely induces immune tolerance to combined hematopoietic cell and organ allografts in humans. Our mouse model required host natural killer T (NKT) cells to induce tolerance. Because NKT cells normally depend on signals from CD8+dendritic cells (DCs) for their activation, we used the mouse model to test the hypothesis that, after lymphoid irradiation, host CD8+DCs play a requisite role in tolerance induction through interactions with NKT cells. Selective deficiency of either CD8+DCs or NKT cells abrogated chimerism and organ graft acceptance. After radiation, the CD8+DCs increased expression of surface molecules required for NKT and apoptotic cell interactions and developed suppressive immune functions, including production of indoleamine 2,3-deoxygenase. Injection of naive mice with apoptotic spleen cells generated by irradiation led to DC changes similar to those induced by lymphoid radiation, suggesting that apoptotic body ingestion by CD8+DCs initiates tolerance induction. Tolerogenic CD8+DCs induced the development of tolerogenic NKT cells with a marked T helper 2 cell bias that, in turn, regulated the differentiation of the DCs and suppressed rejection of the transplants. Thus, reciprocal interactions between CD8+DCs and invariant NKT cells are required for tolerance induction in this system that was translated into a successful clinical protocol.
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, and.
authors.forename: David
authors.initials: D
authors.lastname: Hongo
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, and.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Xiangyue
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, and.|Department of Pathology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Edgar G
authors.initials: EG
authors.lastname: Engleman
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, and.
authors.forename: Samuel
authors.initials: S
authors.lastname: Strober
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D016027:Heart Transplantation; D007108:Immune Tolerance; D051379:Mice; D055611:Natural Killer T-Cells / Q000276:immunology*