GITR activation induces an opposite effect on alloreactive CD4(+) and CD8(+) T cells in graft-versus-host disease.
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.
Muriglan
Stephanie J
SJ
Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, Kettering 425, Mailbox 111, 1275 York Ave., New York, NY 10021, USA.
Ramirez-Montagut
Teresa
T
Alpdogan
Onder
O
Van Huystee
Thomas W
TW
Eng
Jeffrey M
JM
Hubbard
Vanessa M
VM
Kochman
Adam A
AA
Tjoe
Kartono H
KH
Riccardi
Carlo
C
Pandolfi
Pier Paolo
PP
Sakaguchi
Shimon
S
Houghton
Alan N
AN
Van Den Brink
Marcel R M
MR
D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D002455:Cell Division; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006086:Graft vs Host Disease / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015854:Up-Regulation
D053450:Glucocorticoid-Induced TNFR-Related Protein; D015375:Receptors, Interleukin-2; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse