Immune activity varies between individuals. One contributing factor is differing immune set-points—the baseline state that governs the magnitude of immune activation and responsiveness to immune challenges. However, a mechanistic understanding of how an individual’s setpoint is determined is not well defined, which has major therapeutic implications for the treatment of inflammatory and infectious diseases. The Philips Lab investigates how external stimuli establish immune set-points by utilizing multi-omic technologies with genetic models of amplified cytokine signaling to interrogate (1) how STAT-activating mutations perturb cytokine signaling and (2) how these altered signals epigenetically reprogram immune cells to redefine their functional potential. Collectively, our research provides a framework for understanding how altered cytokine signaling reshapes immune set-points and drives heterogeneity in immune responses.