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GITR Triggering Induces Expansion of Both Effector and Regulatory CD4⁺ T Cells In Vivo¹

Ronald W. van Olffen^*, Nathalie Koning^*,, Klaas P. J. M. van Gisbergen^*, Felix M. Wensveen^*, Robert M. Hoek^2,*, Louis Boon, Jörg Hamann^*, Rene A. W. van Lier^* and Martijn A. Nolte^3,*

^* Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy for Arts and Sciences, Amsterdam, The Netherlands; and Bioceros, Utrecht, The Netherlands

Glucocorticoid-induced TNF receptor family-related protein (GITR) is expressed on activated and regulatory T cells, but its role on these functionally opposing cell types is not fully understood. Here we describe that transgenic expression of GITR’s unique ligand (GITRL) induces a prominent increase of both effector and regulatory CD4⁺ T cells, but not CD8⁺ T cells. Regulatory T cells from GITRL transgenic mice are phenotypically activated and retain their suppressive capacity. The accumulation of effector and regulatory T cells is not due to enhanced differentiation of naive T cells, but is a direct result of increased proliferation. Functional consequences of increased numbers of both regulatory and effector T cells were tested in an autoimmune model and show that GITR stimulation is protective, as it significantly delays disease induction. These data indicate that GITR regulates the balance between regulatory and effector CD4⁺ T cells by enhancing proliferation of both populations in parallel.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by a VICI Grant (to R.A.W.v.L.) and a VIDI Grant (to M.A.N.) from The Netherlands Organization of Scientific Research.

² Current address: Department of Neuromedical Genetics, Netherlands Institute for Neuroscience, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands.

³ Address correspondence and reprint requests to Dr. Martijn A. Nolte, Department of Experimental Immunology, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands. E-mail address: m.a.nolte{at}amc.nl

⁴ Abbreviations used in this paper: GITR, Glucocorticoid-induced tumor necrosis factor receptor family-related protein; GITRL, GITR ligand; EAE, experimental autoimmune encephalomyelitis; TG, transgenic; WT, wild type.