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Glucocorticoid-Induced TNF Receptor Expression by T Cells Is Reciprocally Regulated by NF-B and NFAT¹

The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia

Although the transcription factor Foxp3 is implicated in regulating glucocorticoid-induced TNF receptor (GITR) expression in the T regulatory cell lineage, little is known about how GITR is transcriptionally regulated in conventional T cells. In this study, we provide evidence that TCR-mediated GITR expression depends on the ligand affinity and the maturity of conventional T cells. A genetic dissection of GITR transcriptional control revealed that of the three transcription factors downstream of the classical NF-B pathway (RelA, cRel, and NF-B1), RelA is a critical positive regulator of GITR expression, although cRel and NF-B1 also play a positive regulatory role. Consistent with this finding, inhibiting NF-B using Bay11-7082 reduces GITR up-regulation. In contrast, NFAT acts as a negative regulator of GITR expression. This was evidenced by our findings that agents suppressing NFAT activity (e.g., cyclosporin A and FK506) enhanced TCR-mediated GITR expression, whereas agents enhancing NFAT activity (e.g., lithium chloride) suppressed TCR-mediated GITR up-regulation. Critically, the induction of GITR was found to confer protection to conventional T cells from TCR-mediated apoptosis. We propose therefore that two major transcriptional factors activated downstream of the TCR, namely, NF-B and NFAT, act reciprocally to balance TCR-mediated GITR expression in conventional T cells, an outcome that appears to influence cell survival.

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 work was supported by National Health and Medical Research Council of Australia and Juvenile Diabetes Research Foundation (to A.M.L.). Y.Z. is supported by a RD Wright Fellowship from the National Health and Medical Research Council of Australia.

² Address correspondence and reprint requests to Dr. Yifan Zhan and Dr. Andrew M. Lew, Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria, Australia 3050. Email addresses: zhan{at}wehi.edu.au and lew{at}wehi.edu.au

³ Current address: The Macfarlane Burnet Institute for Medical Research and Public Health, Prahran, Victoria 3004, Australia.

⁴ Current address: Bio21 Institute, Melbourne University, Victoria 3010, Australia.

⁵ Abbreviations used in this paper: GITR, glucocorticoid-induced TNFR; Treg, regulatory T cell; DC, dendritic cell; GITRL, GITR ligand; DP, double positive; SP, single positive; fwd, forward; rev, reverse; Tg, transgenic.