Abstract In response to viral infection or vaccination, antigen(Ag)-specific CD8 T cells that are present at low frequencies undergo rapid clonal expansion. While the majority of activated CD8 T cells become terminally differentiated effector T (T ECF) cells following expansion and die after Ag clearance, a small fraction of them persists as memory cells (Tr,1er,:) that contribute to long-term protection. However, it remains incompletely understood how cell-extrinsic stimuli through TCR and cytokine receptors establish the gene regulatory networks that determine the fates of activated CD8 T cells. The overall goal of this grant is to dissect the molecular and cellular mechanisms by which TCR and IL-2R signaling cooperatively regulates CD8 T cell differentiation through the control of the critical transcription factor TCF-1 encoded by Tcf7_ We will test the hypothesize that cooperative action between signals induced by antigen and IL-2, but not IL-15, specifically during priming induces expression of a set of transcription factors and epigenetic changes at a transcriptional silencer element in the Tcf7 locus. The establishment of stable Tcf7 repression requires the stimulationresponsive enhancement of IL-2R signaling, which establishes steady the TEFF- or T MEM-specific gene regulatory circuitry that can be stably maintained after the inducing cell extrinsic stimuli decays as immune responses resolve or become equilibrated. These studies will provide insights into the long standing question of the molecular mechanisms of CD8 T cell differentiation and potential application to programming improved immunotherapies.