The Journal of Immunology, 2007, 178: 85.19.
Copyright © 2007 by The American Association of Immunologists, Inc.
Early CD8 T cell proliferative heterogeneity entails diverse memory differentiation programs
Vandana Kalia1,
Surojit Sarkar1,
Susan M. Kaech2 and
Rafi Ahmed1
1 Microbiology and Immunology, Emory University School of Medicine, 1510 Clifton Road, G211 RRC, Atlanta, GA, 30322,
2 Immunobiology, Yale Medical School, 300 Cedar Street, TAC S641, P.O. Box 208011, New Haven, Connecticut, 06520-8011
Abstract
Initial events governing delineation of the fraction of effector cells that advance into the long-lived memory lineage following antigen clearance remain unclear. We hypothesized that the order of recruitment of naïve CD8 T cells into the immune response regulates the memory potential of an effector cell. To address this hypothesis, we adoptively transferred naïve transgenic P14 CD8 T cells that encode a TCR specific for the GP33-41 epitope of lymphocytic choriomeningitis virus (LCMV) at different days post-infection. As predicted, cells transferred later during an infection demonstrated accelerated acquisition of memory cell phenotype (IL-7RaHi, L-SelectinHi), and proliferated to a greater extent upon secondary challenge compared to cells that were adoptively transferred earlier. Importantly, in a physiologically relevant setting, when cells that had divided < or > 4 divisions (based on CFSE dilution at day 2.5 post-infection) were FACS sorted and their potential to differentiate into long-lived memory cells evaluated, we observed that cells that entered into division later exhibited faster reversion to central memory phenotype, relative to cells that had entered cell division earlier. Memory cells arising from Ag-specific cells that entered proliferation later, also mounted more robust recall proliferative potential compared to those arising from cells that entered proliferation earlier. These data present a model that heterogeneity in early priming events likely dictate heterogeneity in initial proliferation, which in turn regulates their ultimate memory fate.
Supported by Elizabeth Glaser Pediatric AIDS Foundation awards to VK & SS, and NIH & Gates Foundation Grants to RA.
