title: Allospecific rejection of MHC class I-deficient bone marrow by CD8 T cells.
abstract: Avoidance of long-term immunosuppression is a desired goal in organ transplantation. Mixed chimerism offers a promising approach to tolerance induction, and we have aimed to develop low-toxicity, nonimmunodepleting approaches to achieve this outcome. In a mouse model achieving fully MHC-mismatched allogeneic bone marrow engraftment with minimal conditioning (3 Gy total body irradiation followed by anti-CD154 and T cell-depleted allogeneic bone marrow cells), CD4 T cells in the recipient are required to promote tolerance of preexisting alloreactive recipient CD8 T cells and thereby permit chimerism induction. We now demonstrate that mice devoid of CD4 T cells and NK cells reject MHC Class I-deficient and Class I/Class II-deficient marrow in a CD8 T cell-dependent manner. This rejection is specific for donor alloantigens, since recipient hematopoiesis is not affected by donor marrow rejection and MHC Class I-deficient bone marrow that is syngeneic to the recipient is not rejected. Recipient CD8 T cells are activated and develop cytotoxicity against MHC Class I-deficient donor cells in association with rejection. These data implicate a novel CD8 T cell-dependent bone marrow rejection pathway, wherein recipient CD8 T cells indirectly activated by donor alloantigens promote direct killing, in a T cell receptor-independent manner, of Class I-deficient donor cells.
authors.affiliation: Department of Surgery, Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: F
authors.initials: F
authors.lastname: Haspot
authors.forename: H W
authors.initials: HW
authors.lastname: Li
authors.forename: C L
authors.initials: CL
authors.lastname: Lucas
authors.forename: T
authors.initials: T
authors.lastname: Fehr
authors.forename: S
authors.initials: S
authors.lastname: Beyaz
authors.forename: M
authors.initials: M
authors.lastname: Sykes
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000276:immunology; D016026:Bone Marrow Transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006183:H-2 Antigens / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology; D007519:Isoantigens / Q000276:immunology*; D051379:Mice; D018183:Transplantation Chimera; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
chemical_list: D006183:H-2 Antigens; D007519:Isoantigens
keywords: Bone marrow transplantation; CD8 T cells; indirect alloreactivity; tolerance