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Prepublished online as a Blood First Edition Paper on February 6, 2003; DOI 10.1182/blood-2002-11-3577. This Article Full Text (PDF) All Versions of this Article: 2002-11-3577v1 101/11/4260    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Geginat, J. Articles by Sallusto, F. Search for Related Content PubMed PubMed Citation Articles by Geginat, J. Articles by Sallusto, F. Social Bookmarking                   What's this? Submitted November 26, 2002 Accepted January 16, 2003 Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines Jens Geginat*, Antonio Lanzavecchia, and Federica Sallusto Institute for Research in Biomedicine, IRB, Bellinzona, Switzerland * Corresponding author; email: jens.geginat{at}irb.unisi.ch. Four human CD8+ T cell subsets, naive (CCR7+CD45RA+), central memory (TCM, CCR7+CD45RA-), effector memory (TEM, CCR7-CD45RA-) and CD45RA+ effector memory cells (TEMRA, CCR7-CD45RA+) were compared for their capacity to proliferate and differentiate in response to antigen or homeostatic cytokines. Cytokine responsiveness and IL-15 receptor expression was low in naive T cells and progressively increased from TCM to TEM and TEMRA. In contrast, the capacity to accumulate in response to TCR or cytokine stimulation showed a reciprocal pattern and was associated with resistance to cell death and BCL-2 expression. While all TCR-stimulated cells acquired a CD45RA-CCR7- phenotype, cytokine-stimulated cells maintained their phenotype with the exception of TCM, which expressed CCR7, CD45RA and perforin in various combinations. Single CD8+ TCM, but not TEM, could be expanded with cytokines and the obtained clones displayed several distinct phenotypes, suggesting that TCM are heterogeneous. Consistently, CCR4 expression in the CD8+ TCM pool discriminated CCR4+ type 2 polarized cells (Tc2) and CCR4- CTL precursors. Finally, ex vivo Bromodeoxyuridine (BrdU) incorporation experiments revealed that memory subsets have different in vivo proliferation rates, with CCR4- TCM having the highest and TEMRA the lowest turnover. These results show that human CD8+ memory T cell subsets have different proliferation and differentiation potentials in vitro and in vivo. Furthermore they suggest that TEMRA are generated from a TCM subset upon homeostatic proliferation in the absence of antigen. 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