Differential Regulation of TCR‐Induced ZFP36 and ZFP36L1 Expression by Cyclosporin A in CD8 ⁺ T Cells

CD8 + T cells target infected or malignant cells via the production of pro‐inflammatory cytokines and direct target cell killing. Members of the ZFP36‐family of RNA‐binding proteins, ZFP36 and ZFP36L1, regulate these functions in T cells via the regulation of mRNA stability and protein translation. We investigate the regulation of ZFP36 and ZFP36L1 expression using in vitro differentiated OT1 TCR transgenic memory‐like T cells. We characterise the differential kinetics and sensitivity of ZFP36 and ZFP36L1 to antigen affinity and PMA versus ionomycin stimulation. By selectively inhibiting TCR‐induced signalling pathways, we find that p38 MAPK, MEK1/2, and PKC contribute to inducing both ZFP36 and ZFP36L1 expression. By contrast, inhibition of calcineurin using cyclosporin A potently inhibits ZFP36L1 expression while increasing and prolonging ZFP36 expression. The Zfp36 promoter contains many binding sites for the transcription factors ELK‐1/4 and few binding sites for NFAT, while the Zfp36l1 promoter contains many NFAT binding sites and few ELK1/4 binding sites. Our findings suggest that the regulation of divergent transcription factors enables calcineurin to act as a signalling node that mediates the differential regulation of ZFP36 and ZFP36L1 during T cell activation.