Glucocorticoid-induced TNF receptor expression by T cells is reciprocally regulated by NF-kappaB and NFAT.
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-kappaB pathway (RelA, cRel, and NF-kappaB1), RelA is a critical positive regulator of GITR expression, although cRel and NF-kappaB1 also play a positive regulatory role. Consistent with this finding, inhibiting NF-kappaB 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-kappaB and NFAT, act reciprocally to balance TCR-mediated GITR expression in conventional T cells, an outcome that appears to influence cell survival.
Zhan
Yifan
Y
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. zhan@wehi.edu.au
Gerondakis
Steve
S
Coghill
Elise
E
Bourges
Dorothee
D
Xu
Yuekang
Y
Brady
Jamie L
JL
Lew
Andrew M
AM
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D016572:Cyclosporine / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D009570:Nitriles / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000276:immunology*; D013450:Sulfones / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology*
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000276:Adjuvants, Immunologic; D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009570:Nitriles; D011948:Receptors, Antigen, T-Cell; D018124:Receptors, Tumor Necrosis Factor; D013450:Sulfones; D016572:Cyclosporine; D018021:Lithium Chloride; D016559:Tacrolimus