Step-wise epigenetic signal integration governs adaptive programming of cytotoxic lymphocytes

Lymphocyte differentiation depends on activation via antigen and cytokines during the immune response to infection. How the timing and integration of these signals program the epigenetic and functional fate of these cells is not completely understood. In this study, we find that interleukin (IL)-12 signaling received by innate and adaptive lymphocytes has a context-dependent role for immune memory formation. In the absence of a preceding and/or sufficient antigen receptor signaling event, IL-12 impairs the adaptive expansion of cytotoxic lymphocytes. In contrast, sufficient antigen-receptor signaling redirects inflammatory cytokine signals to promote memory differentiation via cooperation of STAT4 and AP-1 transcription factors. By this crucial epigenetic mechanism, optimally equipped lymphocytes are selected for memory formation rather than a terminal effector cell fate. Whereas T cells are hardwired to be shielded from premature IL-12 signaling, NK cells rely on coincidental early antigen receptor signaling for adaptive responses. Together, step-wise integration of antigen and cytokine signaling optimizes both effector and memory differentiation, allowing for promiscuous recruitment into the acute immune response while promoting avidity maturation in memory populations of both innate and adaptive lymphocytes.