Time-dependent regulation of cytokine production by RNA binding proteins defines T cell effector function

Abstract

Potent Tcell responses against infections and malignancies require a rapid yet tightly regulated production of toxic effector molecules. Their production level is defined by post-transcriptional events at 3' untranslated regions (3' UTRs). RNA binding proteins (RBPs) are key regulators in this process. With an RNA aptamer-based capture assay, we identify >130 RBPs interacting with IFNG, TNF, and IL2 3' UTRs in human Tcells. RBP-RNA interactions show plasticity upon Tcell activation. Furthermore, we uncover the intricate and time-dependent regulation of cytokine production by RBPs: whereas HuR supports early cytokine production, ZFP36L1, ATXN2L, and ZC3HAV1 dampen and shorten the production duration, each at different time points. Strikingly, even though ZFP36L1 deletion does not rescue the dysfunctional phenotype, tumor-infiltrating Tcells produce more cytokines and cytotoxic molecules, resulting in superior anti-tumoral Tcell responses. Our findings thus show that identifying RBP-RNA interactions reveals key modulators of Tcell responses in health and disease.