Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 200, Issue 2, Pages 149-157Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20040116
Keywords
transplantation immunology; in vivo annual models; immune regulation; lymphocyte activation; T lymphocyte subsets
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Funding
- NCI NIH HHS [CA58621, P01 CA059350, P01 CA033049, CA33049, CA59350] Funding Source: Medline
- NHLBI NIH HHS [R01 HL72412, R01 HL069929, R01 HL69929, R01 HL072412] Funding Source: Medline
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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.
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