title: IgG antiplatelet immunity is dependent on an early innate natural killer cell-derived interferon-gamma response that is regulated by CD8+ T cells.
abstract: The mechanisms responsible for immunoglobulin G (IgG) immunity against allogeneic platelets are poorly understood. We studied the role that murine recipient CD8+ T and natural killer (NK) cells play in immunity against allogeneic platelets. BALB/c mice were depleted of the cells by cell-specific antibodies, transfused weekly with platelets from C57BL/6 mice, and serum IgG antidonor antibodies were measured by flow cytometry. While allogeneic platelet transfusions into wild-type recipients stimulated IgG antidonor antibodies in all mice by the fifth transfusion, CD8-depleted mice had significantly (P<.001) enhanced antibody production. Isotype analysis revealed that CD8+ T cells suppressed T-helper 2 (Th2)-associated IgG1 but enhanced Th1-associated IgG2a. Compared with wild-type mice, platelet transfusions into CD8-depleted mice stimulated enhanced intracellular interferon (IFN)-gamma production by CD4- lymphocytes within 24 hours after the first transfusion. The early IFN-gamma response correlated with nitric oxide-dependent splenic cytotoxicity (P<.001). In asialo ganglioside monosialic acid 1 (GM1)-depleted mice transfused with allogeneic platelets, the IFN-gamma production, splenic cytotoxicity, and IgG antidonor antibody response were significantly suppressed. These results demonstrate that IgG antiplatelet immunity is dependent on an early NK cell-derived IFN-gamma response that is negatively regulated by CD8+ T cells and suggest that targeting innate NK cell responses may significantly reduce platelet alloimmunization.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, St Michael's Hospital, University of Toronto, ON, Canada.
authors.forename: Ebrahim
authors.initials: E
authors.lastname: Sayeh
authors.forename: Katherine
authors.initials: K
authors.lastname: Sterling
authors.forename: Edwin
authors.initials: E
authors.lastname: Speck
authors.forename: John
authors.initials: J
authors.lastname: Freedman
authors.forename: John W
authors.initials: JW
authors.lastname: Semple
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D005260:Female; D005434:Flow Cytometry; D006706:Homeostasis / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology*; D007518:Isoantibodies / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008212:Lymphocyte Depletion; D034801:Mastocytoma / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017713:Platelet Transfusion; D013945:Thymoma / Q000276:immunology; D013953:Thymus Neoplasms / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D007074:Immunoglobulin G; D007518:Isoantibodies; D007371:Interferon-gamma