Published online March 3, 2008
doi:10.1084/jem.20071641
The Journal of Experimental Medicine, Vol. 205, No. 3, 625-640
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Sarkar et al.
Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates
Surojit Sarkar1,
Vandana Kalia1,
W. Nicholas Haining2,
Bogumila T. Konieczny1,
Shruti Subramaniam1, and
Rafi Ahmed1
1 Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322
2 Pediatric Oncology, Dana-Farber Cancer Institute, Division of Hematology/Oncology, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115
CORRESPONDENCE Rafi Ahmed: ra{at}microbio.emory.edu
An important question in memory development is understanding the differences between effector CD8 T cells that die versus effector cells that survive and give rise to memory cells. In this study, we provide a comprehensive phenotypic, functional, and genomic profiling of terminal effectors and memory precursors. Using killer cell lectin-like receptor G1 as a marker to distinguish these effector subsets, we found that despite their diverse cell fates, both subsets possessed remarkably similar gene expression profiles and functioned as equally potent killer cells. However, only the memory precursors were capable of making interleukin (IL) 2, thus defining a novel effector cell that was cytotoxic, expressed granzyme B, and produced inflammatory cytokines in addition to IL-2. This effector population then differentiated into long-lived protective memory T cells capable of self-renewal and rapid recall responses. Experiments to understand the signals that regulate the generation of terminal effectors versus memory precursors showed that cells that continued to receive antigenic stimulation during the later stages of infection were more likely to become terminal effectors. Importantly, curtailing antigenic stimulation toward the tail end of the acute infection enhanced the generation of memory cells. These studies support the decreasing potential model of memory differentiation and show that the duration of antigenic stimulation is a critical regulator of memory formation.
Abbreviations used: BFA, brefeldin A; GSEA, gene set enrichment analysis; KLRG-1, killer cell lectin-like receptor G 1; LCMV, lymphocytic choriomeningitis virus; MFI, mean fluorescence intensity; p.i., postinfection; Tg, transgenic; VV, vaccinia virus; WT-VV, wild-type VV.
S. Sarkar and V. Kalia contributed equally to this study.
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