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.
Recommended CitationMuriglan, Stephanie J; Ramirez-Montagut, Teresa; Alpdogan, Onder; Van Huystee, Thomas W; Eng, Jeffrey M; Hubbard, Vanessa M; Kochman, Adam A; Tjoe, Kartono H; Riccardi, Carlo; Pandolfi, Pier Paolo; Sakaguchi, Shimon; Houghton, Alan N; and Van Den Brink, Marcel R M, "GITR activation induces an opposite effect on alloreactive CD4(+) and CD8(+) T cells in graft-versus-host disease." (2004). Department of Medical Oncology Faculty Papers. Paper 9.