Regulatory T cells (Tregs) control autoreactive T cells by inhibiting activation-induced proliferation and cytokine expression. The molecular mechanisms responsible for the inactivation of effector T cells by Tregs remain yet to be fully characterized. We report that T-helper cells stimulated in the presence of Tregs quickly activate NFAT1 and have increased NFAT1-dependent expression of the transcription repressor Ikaros. NFAT1 deficiency or dominant-negative Ikaros compromises Treg-mediated inhibition of T-helper cells in vitro and in vivo. Thus, our results place NFAT-dependent mechanisms as general regulators of T-cell tolerance and show that Treg-mediated suppression of T-helper cells results from the activation of NFAT-regulated gene expression.
This study shows that regulatory T cells activate NFAT1-dependent gene expression in stimulated T-helper cells, including the transcription of Ikaros, which is required for optimal T-helper cell suppression in vitro and in vivo.
- Activation of T-helper cells in the presence of tTregs induces the NFAT1-dependent expression if Ikaros, likely as a result of the downmodulation of costimulatory ligands in antigen-presenting cells.
- NFAT1-deficient CD4+ T cells or T cells expressing a dominant-negative form of Ikaros are resistant to tTreg-mediated suppression.