Zfp36l1 establishes the high affinity CD8 T cell response by directly linking TCR affinity to cytokine sensing

The T cell effector phase is dominated by few T cells with high affinity TCR for the respective immunodominant antigen. During priming T cells have to process multiple cues in form of antigen, costimulation and cytokines, thus a plethora of T cells with different specificities and affinities has to compete for these cues. IL2 has been suggested to be a pivotal pleiotropic molecule which organizes the quantity, quality and clonal composition of T cells contributing to the effector response. How individual T cells compete for and respond to IL2 and other key cytokines at the molecular level and as a consequence, how this competition shapes population dynamics is still poorly understood. Here we describe how the RNA binding protein ZFP36L1 acts as a sensor of antigen affinity and establishes dominance of high affinity T cells by promoting the response to IL2. Overall design: RNA-seq libraries were prepared from OT-I transgenic naïve CD8+ Tcells, following stimulation for 0, 1.5, 3, 6 or 16h, with 2-3 replicates for control and Zfp36/Zfp36l1 double KO mice. 500.000 cells in 0.2ml IMDM+10%FCS, 50uM beta-Me and 40U Penicillin /Streptomycin were stimulated with 0.1nM N4 peptide. Samples with corresponding genotype and replicate number were from the same mouse: except for WT1/WT4, sufficient cells were obtained such that libraries could be generated for all five timepoints from a single mouse.