Molecular events driving naive T cell activation and subsequent effector differentiation. (A) Antigen-dependent stimulation of the TCR (signal 1) on a naive T cell combined with CD28-mediated costimulation (signal 2) results in the activation of NFAT, AP-1, and NF-κB TFs that increase chromatin accessibility at regulatory elements controlling genes important for T cell activation. These include genes encoding IL-2 and its high-affinity receptor, which then establish an autocrine positive feedback loop that activates the STAT5 TF. In cooperation with the TCR-induced TFs, STAT5 is critical for chromatin remodeling and full activation of the general activation program. (B and C) After initial activation, exposure to specific cytokines (signal 3) induces effector cell differentiation toward specific Th (panel B) or cytotoxic T (Tc; panel C) cell subsets. These cytokines activate specific members of the STAT TF family that in turn activate lineage-defining TFs (i.e., T-bet, GATA3, RORγt, EOMES, and RUNX3), which team up with STAT proteins and TCR-induced TFs to activate the different effector programs.