Reciprocal responsiveness to interleukin-12 and interferon-α specifies human CD8⁺ effector versus central memory T-cell fates

Multiple innate signals regulate the genesis of effector and memory CD8⁺ T cells. In this study, we demonstrate that the innate cytokines interleukin (IL)-12 and interferon (IFN)-α/β regulate distinct aspects of effector and memory human CD8⁺ T-cell differentiation. IL-12 exclusively promoted the development of IFN-γ- and tumor necrosis factor (TNF)-α-secreting T effector memory (T_EM) cells, whereas IFN-α drove the development of T central memory (T_CM) cells. The development of T_EM and T_CM was linked to cell division. In rapidly dividing cells, IL-12 programmed T_EM through induction of the IL-12 receptor β2. In contrast, IFN-α regulated T_CM development by slowing the progression of cell division in a subpopulation of cells that selectively expressed elevated IFN-α/β receptor-2. The strength of signal delivered through T-cell receptor (TCR) engagement regulated the responsiveness of cells to IL-12 and IFN-α. In the presence of both IL-12 and IFN-α, these cytokine signals were amplified as the strength of the TCR signal was increased, promoting the simultaneous development of both T_CM and T_EM. Together, our results support a novel model in which IL-12 and IFN-α act in a nonredundant manner to regulate the colinear generation of both effector and memory cells.