NK cells mediate reduction of GVHD by inhibiting activated, alloreactive T cells while retaining GVT effects

Blood. 2010 May 27;115(21):4293-301. doi: 10.1182/blood-2009-05-222190. Epub 2010 Mar 16.


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

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Bone Marrow Transplantation
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cytokines / biosynthesis
  • Fas Ligand Protein / deficiency
  • Fas Ligand Protein / genetics
  • Fas Ligand Protein / immunology
  • Female
  • Graft vs Host Disease / immunology*
  • Graft vs Host Disease / prevention & control*
  • Graft vs Tumor Effect / immunology*
  • Inflammation Mediators / metabolism
  • Interferon-gamma / deficiency
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / transplantation
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Pore Forming Cytotoxic Proteins / deficiency
  • Pore Forming Cytotoxic Proteins / genetics
  • Pore Forming Cytotoxic Proteins / immunology
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / transplantation
  • T-Lymphocytes, Regulatory / immunology
  • Transplantation, Homologous


  • Cytokines
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Il2ra protein, mouse
  • Inflammation Mediators
  • Interleukin-2 Receptor alpha Subunit
  • Pore Forming Cytotoxic Proteins
  • perforin, mouse
  • Interferon-gamma