Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells
- Masahide Tone*,
- Yukiko Tone,
- Elizabeth Adams,
- Stephen F. Yates,
- Mark R. Frewin,
- Stephen P. Cobbold, and
- Herman Waldmann*
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom
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Edited by N. Avrion Mitchison, University College London, London, United Kingdom (received for review August 1, 2003)
Abstract
Recently, agonist antibodies to glucocorticoid-induced tumor necrosis factor receptor (GITR) (tumor necrosis factor receptor superfamily 18) have been shown to neutralize the suppressive activity of CD4+CD25+ regulatory T cells. It was anticipated that this would be the role of the physiological ligand. We have identified and expressed the gene for mouse GITR ligand and have confirmed that its interaction with GITR reverses suppression by CD4+CD25+ T cells. It also, however, provides a costimulatory signal for the antigen-driven proliferation of naïve T cells and polarized T helper 1 and T helper 2 clones. RT-PCR and mAb staining revealed mouse GITR ligand expression in dendritic cells, macrophages, and B cells. Expression was controlled by the transcription factor NF-1 and potentially by alternative splicing of mRNA destabilization sequences.
Footnotes
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↵ * To whom correspondence should be addressed. E-mail: masahide.tone{at}path.ox.ac.uk or herman.waldmann{at}path.ox.ac.uk.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: GITR, glucocorticoid-induced tumor necrosis factor receptor; mGITR, mouse GITR; mGITRL, mouse GITR ligand; hGITR, human GITR; hCD40L, human CD40 ligand; EMSA, electrophoretic mobility-shift assay; HPRT, hypoxanthine phosphoribosyltransferase; LPS, lipopolysaccharide; TCR, T cell receptor; bm, bone marrow-derived; DC, dendritic cells; Th1, T helper 1; Th2, T helper 2.
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Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. AJ577579, AJ577580, and AJ577581).
- Copyright © 2003, The National Academy of Sciences
