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Published online 12 July 2004 doi:10.1084/jem.20040116
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 2, 149-157
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GITR Activation Induces an Opposite Effect on Alloreactive CD4+ and CD8+ T Cells in Graft-Versus-Host Disease

Stephanie J. Muriglan1, Teresa Ramirez-Montagut1, Onder Alpdogan1, Thomas W. van Huystee1, Jeffrey M. Eng1, Vanessa M. Hubbard1, Adam A. Kochman1, Kartono H. Tjoe1, Carlo Riccardi3, Pier Paolo Pandolfi2, Shimon Sakaguchi4,5, Alan N. Houghton1, and Marcel R.M. van den Brink1

1 Department of Medicine and Immunology and 2 Department of Pathology, Memorial Sloan-Kettering Cancer, New York, NY 10021
3 Department of Clinical and Experimental Medicine, Perugia University Medical School, 06100 Perugia, Italy
4 Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
5 Laboratory for Immunopathology, Institute of Physical and Chemical Research, Research Center for Allergy and Immunology, Yokohama 230-0045, Japan

Address correspondence to Teresa Ramirez-Montagut, Memorial Sloan-Kettering Cancer Center, Kettering 425, Mailbox 111, 1275 York Ave., New York, NY 10021. Phone: (212) 639-5607; Fax: (917) 432-2375; email: ramirezt{at}mskcc.org

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.

Key Words: transplantation immunology • in vivo animal models • immune regulation • lymphocyte activation • T lymphocyte subsets

S.J. Muriglan and T. Ramirez-Montagut contributed equally to this work.

This work was presented at the American Society of Hematology Annual Meeting in 2003, the American Society for Blood and Marrow Transplantation in 2004, the American Association for Cancer Research Annual Meeting in 2004, and the American Association for Immunologists in 2004 in abstract form.

Abbreviations used in this paper: AICD, activation-induced cell death; BMT, BM transplantation; CFSE, carboxyfluorescein succinimidyl ester; GITR, glucocorticoid-induced tumor necrosis factor receptor family-related gene; GITRL, GITR ligand; sGITR, soluble GITR; TCD, T cell–deleted.


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