GITR activation induces an opposite effect on alloreactive CD4+ and CD8+ T cells in graft-versus-host disease Academic Article uri icon


MeSH Major

  • CD4-Positive T-Lymphocytes
  • CD8-Positive T-Lymphocytes
  • Graft vs Host Disease
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor


  • Glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR) is a member of the tumor necrosis factor receptor (TNFR) family that is expressed at low levels on unstimulated T cells, B cells, and macrophages. Upon activation, CD4(+) and CD8(+) T cells up-regulate GITR expression, whereas immunoregulatory T cells constitutively express high levels of GITR. Here, we show that GITR may regulate alloreactive responses during graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). Using a BMT model with major histocompatibility complex class I and class II disparity, we demonstrate that GITR stimulation in vitro and in vivo enhances alloreactive CD8(+)CD25(-) T cell proliferation, whereas it decreases alloreactive CD4(+)CD25(-) proliferation. Allo-stimulated CD4(+)CD25(-) cells show increased apoptosis upon GITR stimulation that is dependent on the Fas-FasL pathway. Recipients of an allograft containing CD8(+)CD25(-) donor T cells had increased GVHD morbidity and mortality in the presence of GITR-activating antibody (Ab). Conversely, recipients of an allograft with CD4(+)CD25(-) T cells showed a significant decrease in GVHD when treated with a GITR-activating Ab. Our findings indicate that GITR has opposite effects on the regulation of alloreactive CD4(+) and CD8(+) T cells.

publication date

  • July 19, 2004



  • Academic Article



  • eng

PubMed Central ID

  • PMC2212013

Digital Object Identifier (DOI)

  • 10.1084/jem.20040116

PubMed ID

  • 15249593

Additional Document Info

start page

  • 149

end page

  • 57


  • 200


  • 2