Preferential involvement of Tim-3 in the regulation of hepatic CD8+ T cells in murine acute graft-versus-host disease

J Immunol. 2006 Oct 1;177(7):4281-7. doi: 10.4049/jimmunol.177.7.4281.


Tim-3, a member of the T cell Ig mucin (TIM) family regulates effector Th1 responses. We examined Tim-3 and its ligand expression as well as the effects of anti-Tim-3 mAb treatment in a murine model of acute graft-vs-host disease (aGVHD). In mice with aGVHD, Tim-3 expression was markedly up-regulated on splenic and hepatic CD4+ and CD8+ T cells, dendritic cells (DCs), and macrophages, and this was especially dramatic in hepatic CD8+ T cells. Both donor- and host-derived CD8+ T cells induced similar levels of Tim-3. Tim-3 ligand expression was also up-regulated in splenic T cells, DCs, and macrophages, but not in the hepatic lymphocytes. The administration of anti-Tim-3 mAbs accelerated aGVHD, as demonstrated by body weight loss, reduction in total splenocyte number, and infiltration of lymphocytes in the liver. IFN-gamma expression by splenic and hepatic CD4+ and CD8+ T cells was significantly augmented by anti-Tim-3 mAb treatment. In addition, the cytotoxicity against host alloantigen by donor CD8+ T cells was enhanced. These results demonstrate that the anti-Tim-3 treatment in aGVHD augmented the activation of effector T cells expressing IFN-gamma or exerting cytotoxicity. Our results suggest that Tim-3 may play a crucial role in the regulation of CD8+ T cells responsible for the maintenance of hepatic homeostasis and tolerance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal
  • CD4 Antigens / immunology
  • CD4 Antigens / metabolism
  • CD8 Antigens / immunology
  • CD8 Antigens / metabolism
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Disease Models, Animal
  • Female
  • Fluorescent Antibody Technique
  • Graft vs Host Disease / immunology*
  • Hepatitis A Virus Cellular Receptor 2
  • Immune Tolerance*
  • Interferon-gamma / biosynthesis
  • Liver / cytology
  • Liver / immunology
  • Liver Transplantation / immunology*
  • Lymphocyte Activation / immunology*
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Receptors, Virus / immunology*
  • Spleen / cytology
  • Spleen / immunology
  • T-Lymphocytes / immunology*
  • Transfection


  • Antibodies, Monoclonal
  • CD4 Antigens
  • CD8 Antigens
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Receptors, Virus
  • Interferon-gamma