Abstract
Natural killer (NK) cells suppress graft-versus-host disease (GVHD) without causing GVHD themselves. Our previous studies demonstrated that allogeneic T cells and NK cells traffic similarly after allogeneic bone marrow transplantation (BMT). We therefore investigated the impact of donor NK cells on donor alloreactive T cells in GVHD induction. Animals receiving donor NK and T cells showed improved survival and decreased GVHD score compared with controls receiving donor T cells alone. Donor T cells exhibited less proliferation, lower CD25 expression, and decreased interferon-gamma (IFN-gamma) production in the presence of NK cells. In vivo, we observed perforin- and Fas ligand (FasL)-mediated reduction of donor T cell proliferation and increased T cell apoptosis in the presence of NK cells. Further, activated NK cells mediated direct lysis of reisolated GVHD-inducing T cells in vitro. The graft-versus-tumor (GVT) effect was retained in the presence of donor NK cells. We demonstrate a novel mechanism of NK cell-mediated GVHD reduction whereby donor NK cells inhibit and lyse autologous donor T cells activated during the initiation of GVHD.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Apoptosis
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Bone Marrow Transplantation
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CD4-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / immunology
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Cytokines / biosynthesis
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Fas Ligand Protein / deficiency
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Fas Ligand Protein / genetics
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Fas Ligand Protein / immunology
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Female
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Graft vs Host Disease / immunology*
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Graft vs Host Disease / prevention & control*
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Graft vs Tumor Effect / immunology*
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Inflammation Mediators / metabolism
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Interferon-gamma / deficiency
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Interferon-gamma / genetics
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Interferon-gamma / immunology
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Interleukin-2 Receptor alpha Subunit / immunology
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Killer Cells, Natural / immunology*
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Killer Cells, Natural / transplantation
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Lymphocyte Activation
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Pore Forming Cytotoxic Proteins / deficiency
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Pore Forming Cytotoxic Proteins / genetics
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Pore Forming Cytotoxic Proteins / immunology
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T-Lymphocytes / cytology
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T-Lymphocytes / immunology*
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T-Lymphocytes / transplantation
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T-Lymphocytes, Regulatory / immunology
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Transplantation, Homologous
Substances
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Cytokines
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Fas Ligand Protein
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Fasl protein, mouse
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Il2ra protein, mouse
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Inflammation Mediators
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Interleukin-2 Receptor alpha Subunit
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Pore Forming Cytotoxic Proteins
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perforin, mouse
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Interferon-gamma