Batf3 is a critical transcription factor in IL-2 mediated programming of CD8+ T cell memory.

Abstract

Abstract CD8+ T cell activation triggers chromatin remodeling and transcription factor (TF) binding, leading to differentiation into effector (TEFF) and a spectrum of memory (TMEM) phenotypes. Previous studies have found modified chromatin accessibility at loci encoding Basic Leucine Zipper (bZIP) family motifs; however, specific mechanisms of transcriptional regulation by these TFs to program TMEM are not fully understood. During TCR stimulation, transient upregulation of bZIP TF Batf3 is accompanied by binding of genomic loci encoding its motif. Nascent RNA sequencing of IL-2Rα-/- CD8+T cells shows that Batf3 upregulation upon TCR stimulation is highly dependent on IL-2R signaling. Constitutive loss of either IL-2Rα or Batf3 results in decreased survival of CD8+ T cells during the transition from effector to memory phase of acute LCMVArm infection, and reduced immunological memory towards infection re-challenge. We find that enforced overexpression of Batf3 cDNA using a retroviral vector in virus-specific IL-2Rα-/- CD8+ T cells greatly enhanced their capacity for survival into the contraction phase of primary infection. Upon secondary infection, ectopic Batf3 expression rescued the proliferation defect seen in IL-2Rα-/- CD8+ T cells. These results suggest that Batf3 plays a crucial role within the IL-2R signal transduction cascade during CD8+ T cell activation to promote enhanced cell survival into the memory phase of infection response.