Stepwise epigenetic signal integration drives adaptive programming of cytotoxic lymphocytes

Lymphocyte differentiation during infection depends on the integration of antigen and cytokine signals, yet how the timing and sequence of these cues program cell fate remains unclear. We found that interleukin-12 (IL-12) plays a context-dependent role in immune memory formation. Without prior antigen-receptor signaling, IL-12 drove cytotoxic lymphocytes toward terminal effector differentiation. In contrast, antigen signaling redirected IL-12-STAT4 activity through cooperation with AP-1 transcription factors to promote memory formation. This stepwise signal integration enabled lymphocytes to acquire memory rather than effector fates. Whereas CD8⁺ T cells were protected from premature IL-12 signaling by delayed receptor expression, natural killer (NK) cells, which constitutively express the IL-12 receptor, must engage their antigen receptor before cytokine signaling for efficient adaptive programming. Together, these findings define a framework in which sequential antigen and cytokine signaling coordinates effector versus memory differentiation, ensuring both robust primary responses and selective enrichment of high-avidity memory clones.