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Glucocorticoid-induced TNF receptor expression by T cells is reciprocally regulated by NF-kappa B and NFAT


Zhan, YF; Gerondakis, S; Coghill, E; Bourges, D; Xu, YK; Brady, JL; Lew, AM
2008-10-15
JOURNAL OF IMMUNOLOGY
Journal Article
181
8
5405-5413
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-kappa B pathway (RelA, cRel, and NF-kappa B1), RelA is a critical positive regulator of GITR expression, although cRel and NF-kappa B1 also play a positive regulatory role. Consistent with this finding, inhibiting NF-kappa 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 upregulation. 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-kappa B and NFAT, act reciprocally to balance TCR-mediated GITR expression in conventional T cells, an outcome that appears to influence cell survival.
AMER ASSOC IMMUNOLOGISTS
TRANSCRIPTION FACTOR NFAT1; GENE-EXPRESSION; COSTIMULATORY RECEPTOR; BINDING PROTEIN; CYCLOSPORINE-A; NUCLEAR FACTOR; MOUSE GITR; ACTIVATION; FAMILY; MEMBER
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