Submitted November 7, 2008
Accepted March 14, 2009
Reciprocal responsiveness to IL-12 and IFN-
specifies human CD8+ effector versus central memory T cell fates
Hilario J. Ramos, Ann M. Davis, Alexander G. Cole, John D. Schatzle, James Forman, and J. David Farrar*
Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, TX, United States
Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX, United States
Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, TX, United States
* Corresponding author; email: david.farrar{at}utsouthwestern.edu.
Multiple innate signals regulate the genesis of effector and memory CD8+ T cells. In this study, we demonstrate that the innate cytokines IL-12 and IFN-
/
regulate distinct aspects of effector and memory human CD8+ T cell differentiation. IL-12 exclusively promoted the development of IFN-
- and TNF--secreting effector memory TEM cells, whereas, IFN- drove the development of central memory TCM cells. The development of TEM and TCM was linked to cell division. In rapidly dividing cells, IL-12 programmed TEM through induction of the IL-12 receptor 2 (IL-12R2). In contrast, IFN- regulated TCM development by slowing the progression of cell division in a subpopulation of cells that selectively expressed elevated IFN-/ receptor-2 (IFNAR2). The strength of signal delivered through TCR engagement regulated the responsiveness of cells to IL-12 and IFN-. In the presence of both IL-12 and IFN-, these cytokine signals were amplified as the strength of the TCR signal was increased, promoting the simultaneous development of both TCM and TEM. Together, our results support a novel model in which IL-12 and IFN- act in a non-redundant manner to regulate the co-linear generation of both effector and memory cells.
