Abstract
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)-alpha/beta regulate distinct aspects of effector and memory human CD8+ T-cell differentiation. IL-12 exclusively promoted the development of IFN-gamma- and tumor necrosis factor (TNF)-alpha-secreting T effector memory (T(EM)) cells, whereas IFN-alpha 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 beta2. In contrast, IFN-alpha regulated T(CM) development by slowing the progression of cell division in a subpopulation of cells that selectively expressed elevated IFN-alpha/beta receptor-2. The strength of signal delivered through T-cell receptor (TCR) engagement regulated the responsiveness of cells to IL-12 and IFN-alpha. In the presence of both IL-12 and IFN-alpha, 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-alpha act in a nonredundant manner to regulate the colinear generation of both effector and memory cells.