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* Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne Branch, University Hospital of Lausanne, Lausanne, Switzerland;
Medical Oncology, Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland;
Swiss Institute for Experimental Cancer Research, Epalinges, Switzerland;
Columbia University Medical Center, Irving Cancer Research Center, New York, NY 10032; and
¶ Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129
In humans, the pathways of memory and effector T cell differentiation remain poorly defined. We have dissected the functional properties of ex vivo effector-memory (EM) CD45RA–CCR7– T lymphocytes present within the circulating CD8+ T cell pool of healthy individuals. Our studies show that EM T cells are heterogeneous and are subdivided based on differential CD27 and CD28 expression into four subsets. EM1 (CD27+CD28+) and EM4 (CD27–CD28+) T cells express low levels of effector mediators such as granzyme B and perforin and high levels of CD127/IL-7R
. EM1 cells also have a relatively short replicative history and display strong ex vivo telomerase activity. Therefore, these cells are closely related to central-memory (CD45RA–CCR7+) cells. In contrast, EM2 (CD27+CD28–) and EM3 (CD27–CD28–) cells express mediators characteristic of effector cells, whereby EM3 cells display stronger ex vivo cytolytic activity and have experienced larger numbers of cell divisions, thus resembling differentiated effector (CD45RA+CCR7–) cells. These data indicate that progressive up-regulation of cytolytic activity and stepwise loss of CCR7, CD28, and CD27 both characterize CD8+ T cell differentiation. Finally, memory CD8+ T cells not only include central-memory cells but also EM1 cells, which differ in CCR7 expression and may therefore confer memory functions in lymphoid and peripheral tissues, respectively.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was sponsored and supported by the Swiss National Center of Competence in Research Molecular Oncology and Swiss National Science Foundation Grants 3100-068016 and 3100A0-105929. A.Z. was supported in part by the Emmy-Noether Program of the Deutsche Forschungsgemeinshaft (Zi-685/2.3) and a grant from the Swiss National Foundation (3200B0-103608/1).
2 Address correspondence and reprint requests to Dr. Nathalie Rufer, Swiss Institute for Experimental Cancer Research, 155 ch. des Boveresses, CH-1066 Epalinges, Switzerland. E-mail address: Nathalie.Rufer{at}isrec.ch
3 Abbreviations used in this paper: CM, central-memory; EM, effector-memory; sj, signal joint; TRAP, telomerase repeat amplification protocol; FISH, fluorescence in situ hybridization; HD, healthy donor; TREC, TCR excision circle.
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