Basal level of ATF4 promotes T cell readiness for activation-induced proliferation [ATAC-seq]

Stress responding elements such as eIF2α phosphorylation are either upregulated or required during late-phase T cell activation and differentiation. However, it is not well understood whether these elements are essential within the first 12-24 hours post-stimulation, a period when mitochondrial activation and metabolic reprogramming are critical. Here, we demonstrate that T cell activation-induced mTOR and GCN2 phosphorylation leads to the upregulation of ATF4 protein as early as 12 hours after stimulation. This early induction of ATF4 has transcriptional activities that positively or negatively regulate stress response, signaling, and metabolism. Loss of Atf4 in T cells alters transcriptome dynamics, impairs amino acid transport and biosynthesis, and disrupts cellular adaptive responses to ER stress and oxidative stress. It also hinders cell growth, resulting in defective effector cell differentiation in vitro or in vivo in a chronic LCMV infection model. Our findings suggest that a basal level of ATF4 during the early phase of T cell activation enhances the preparedness of cells to cope with integrated nutritional, protein folding, and oxidative stresses during the activation course. This, in turn, protects cells from stress-related cell death or senescence.