Basal level of ATF4 promotes T cell readiness for activation-induced proliferation

Stress-response elements are required during late-phase T cell activation and differentiation. To investigate whether they are indispensable during the first 12-24 h post-stimulation when mitochondrial activation and metabolic reprogramming are critical, we activated <i>Atf4</i>-sufficient and <i>Atf4</i>-deficient T cells and tracked their earliest activation dynamics. We demonstrate that T cell activation-induced mTOR and GCN2 phosphorylation leads to the upregulation of ATF4 protein as early as 12 h after stimulation. This early induction of ATF4 has transcriptional activities that regulate stress response, signaling, and metabolism. Loss of <i>Atf4</i> in T cells alters transcriptome dynamics, impairs amino acid transport and biosynthesis, and disrupts adaptive responses to ER stress and oxidative stress, resulting in defective effector cell differentiation <i>in vitro</i> or <i>in vivo</i>. 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 stresses during the activation course.