A Rapid Translational Immune Response Program in CD8 Memory T Lymphocytes

Abstract: Immune cell activation is a very rapid and concerted cellular response that requires coordination between cellular processes that occur in different compartments and on very different time scales. Here, we use ribosome profiling and deep RNA sequencing to define the acute mRNA translation changes that follow initial signaling events and enable subsequent events of T cell activation and expansion. Briefly, early events in the activation of antigen experienced CD 8 T cells are insensitive to transcriptional blockade with actinomycin, and instead depend on the translation of pre-existing mRNAs and blocked by cycloheximide. Ribosome profiling identifies ~92 mRNAs that are recruited into ribosomes following CD8 T cell stimulation. These mRNAs typically have structured GC and pyrimidine rich 5’UTRs and they encode key regulators of T cell activation and proliferation such as Notch1, Ifngr1, Il2rb, serine metabolism enzymes Psat1 and Shmt2, and translation factors eEF1a1 and eEF2. The increased production of receptors of IL2 and IFNγ precedes the activation of gene expression and augments cellular signals and T cell activation. Together, we identify the early RNA translation program that acts in a feed-forward manner to enable the rapid and dramatic process of CD8 T cell expansion and activation. mRNA and Ribosome footprints of CD8 memory T cells before and after two hours after CD3/CD28 stimulation