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

   

Authors:	Muriglan, S. J.; Ramirez-Montagut, T.; Alpdogan, O.; Van Huystee, T.; Eng, J. M.; Hubbard, V. M.; Kochman, A. A.; Tjoe, K. H.; Riccardi, C.; Pandolfi, P. P.; Sakaguchi, S.; Houghton, A. N.; van den Brink, M. R. M.
Article Title:	GITR activation induces an opposite effect on alloreactive CD4+ and CD8+ T cells in graft-versus-host disease
Abstract:	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.
Keywords:	controlled study; protein expression; mortality; nonhuman; flow cytometry; cd8 antigen; cell proliferation; t lymphocyte; cd8-positive t-lymphocytes; animal cell; mouse; animals; mice; animal tissue; gene; cell division; apoptosis; gene expression; morbidity; animal experiment; animal model; mice, inbred balb c; mice, inbred c57bl; b lymphocyte; immunoregulation; lymphocyte activation; cd4-positive t-lymphocytes; graft versus host reaction; glucocorticoid; tumor necrosis factor receptor; upregulation; cd4 antigen; enzyme-linked immunosorbent assay; up-regulation; macrophage; bone marrow transplantation; graft vs host disease; transplantation immunology; receptors, tumor necrosis factor; alloimmunity; histocompatibility; receptors, interleukin-2; receptors, nerve growth factor; immune regulation; female; priority journal; article; in vivo animal models; t lymphocyte subsets
Journal Title:	Journal of Experimental Medicine
Volume:	200
Issue:	2
ISSN:	0022-1007
Publisher:	Rockefeller University Press
Date Published:	2004-07-19
Start Page:	149
End Page:	157
Language:	English
DOI:	10.1084/jem.20040116
PROVIDER:	scopus
PMCID:	PMC2212013
PUBMED:	15249593
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-3242800449&partnerID=40&md5=d65bcbd45cab2f5a986b58e4fe2582a4
Notes:	J. Exp. Med. -- Cited By (since 1996):71 -- Export Date: 16 June 2014 -- CODEN: JEMEA -- Source: Scopus

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