Regulation of IFNγ production by ZFP36L2 in T cells is context-dependent

Abstract

CD8+ T cells kill target cells by releasing cytotoxic molecules and pro-inflammatory cytokines, such as TNF and IFNgamma. The magnitude and duration of cytokine production is defined by post-transcriptional regulation, and a critical regulator herein are RNA-binding proteins (RBPs). Although the functional importance of RBPs in regulating cytokine production is established, the kinetics and mode of action through which RBPs control cytokine production is not well understood. Previously, we showed that the RBP ZFP36L2 blocks translation of pre-formed cytokine encoding mRNA in quiescent memory T cells. Here, we uncover that ZFP36L2 regulates cytokine production in a context-dependent manner. T cell-specific deletion of ZFP36L2 (CD4-cre) had no effect on T cell development, or on cytokine production during early time points (2-6h) of T cell activation. In contrast, ZFP36L2 specifically dampened the production of IFNamma during prolonged T cell activation (20-48h). ZFP36L2 deficiency also resulted in increased production of IFNgamma production in tumour-infiltrating T cells that are chronically exposed to antigen. Mechanistically, ZFP36L2 regulates IFNgamma production at late time points of activation by destabilizing Ifng mRNA in an AU-rich element-dependent manner. Together, our results reveal that ZFP36L2 employs different regulatory nodules in effector and memory T cells to regulate cytokine production.