GVHD prevents NK-cell–dependent leukemia and virus-specific innate immunity
| Autor: | Peter Fleming, Antiopi Varelias, Siok-Keen Tey, Mariapia A. Degli-Esposti, Kelli P. A. MacDonald, Bruce R. Blazar, Fernando Souza-Fonseca-Guimaraes, Rachel D. Kuns, Mark J. Smyth, Kelly R. Locke, Geoffrey R. Hill, Steven W. Lane, Katie E. Lineburg, Nicholas D. Huntington, Iona S. Schuster, Mark D. Bunting |
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| Rok vydání: | 2017 |
| Předmět: |
CD4-Positive T-Lymphocytes
0301 basic medicine Immunology Cytomegalovirus Graft vs Host Disease chemical and pharmacologic phenomena CD8-Positive T-Lymphocytes Biology Biochemistry 03 medical and health sciences 0302 clinical medicine Immune system immune system diseases Immunity Cell Line Tumor Autophagy medicine Animals Humans Transplantation Homologous Bone Marrow Transplantation Interleukin-15 Mice Inbred BALB C Transplantation Leukemia Innate immune system Cell Biology Hematology medicine.disease Acquired immune system Immunity Innate Killer Cells Natural Mice Inbred C57BL surgical procedures operative 030104 developmental biology Graft-versus-host disease Interleukin 15 Cytomegalovirus Infections Female 030215 immunology |
| Zdroj: | Blood. 129:630-642 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2016-08-734020 |
| Popis: | Allogeneic bone marrow transplantation (allo-BMT) is a curative therapy for hematological malignancies, but is associated with significant complications, principally graft-versus-host disease (GVHD) and opportunistic infections. Natural killer (NK) cells mediate important innate immunity that provides a temporal bridge until the reconstruction of adaptive immunity. Here, we show that the development of GVHD after allo-BMT prevented NK-cell reconstitution, particularly within the maturing M1 and M2 NK-cell subsets in association with exaggerated activation, apoptosis, and autophagy. Donor T cells were critical in this process by limiting the availability of interleukin 15 (IL-15), and administration of IL-15/IL-15Rα or immune suppression with rapamycin could restore NK-cell reconstitution. Importantly, the NK-cell defect induced by GVHD resulted in the failure of NK-cell-dependent in vivo cytotoxicity and graft-versus-leukemia effects. Control of cytomegalovirus infection after allo-BMT was also impaired during GVHD. Thus, during GVHD, donor T cells compete with NK cells for IL-15 thereby inducing profound defects in NK-cell reconstitution that compromise both leukemia and pathogen-specific immunity. |
| Databáze: | OpenAIRE |
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