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Blood, 28 May 2009, Vol. 113, No. 22, pp. 5516-5525.
Prepublished online as a Blood First Edition Paper on March 18, 2009; DOI 10.1182/blood-2008-11-188458.
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IMMUNOBIOLOGY
Reciprocal responsiveness to interleukin-12 and interferon- specifies human CD8+ effector versus central memory T-cell fates
Hilario J. Ramos1,
Ann M. Davis1,
Alexander G. Cole1,
John D. Schatzle1,2,
James Forman1, and
J. David Farrar1,3
Departments of 1 Immunology,
2 Pathology, and
3 Molecular Biology, University of Texas Southwestern Medical Center, Dallas
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)– /β regulate distinct aspects of effector and memory human CD8+ T-cell differentiation. IL-12 exclusively promoted the development of IFN- – and tumor necrosis factor (TNF)––secreting T effector memory (TEM) cells, whereas IFN- drove the development of T 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 β2. In contrast, IFN- regulated TCM development by slowing the progression of cell division in a subpopulation of cells that selectively expressed elevated IFN-/β receptor-2. The strength of signal delivered through T-cell receptor (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 nonredundant manner to regulate the colinear generation of both effector and memory cells.
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