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

## TL;DR

This study explores how cyclosporin A affects the expression of ZFP36 and ZFP36L1 in CD8+ T cells, revealing distinct regulatory mechanisms.

## Contribution

The study identifies calcineurin as a key signaling node that differentially regulates ZFP36 and ZFP36L1 through distinct transcription factors.

## Key findings

- Cyclosporin A inhibits ZFP36L1 expression while increasing ZFP36 expression in CD8+ T cells.
- ZFP36 and ZFP36L1 promoters have distinct transcription factor binding sites, influencing their regulation.
- p38 MAPK, MEK1/2, and PKC contribute to the induction of both ZFP36 and ZFP36L1 expression.

## Abstract

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.

Proposed mechanism underlying the repression of ZFP36 and induction of ZFP36L1 by calcineurin. ELK‐1 is activated by stimuli and promotes the transcription of Zfp36. Calcineurin dephosphorylates active ELK‐1 to inhibit its positive effect on Zfp36 transcription, while promoting NFAT‐mediated Zfp36l1 transcription.