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* Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland;
Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland;
Swiss Institute for Experimental Cancer Research, Epalinges, Switzerland; and
National Center for Competence in Research, Molecular Oncology, Epalinges, Switzerland
Activated CD8 T cells develop cytotoxicity against autologous cells bearing foreign Ags and self/tumor Ags. However, self-specific cytolysis needs to be kept under control to avoid overwhelming immunopathology. After peptide vaccination of melanoma patients, we studied molecular and functional properties of T cell subsets specific for the self/tumor Ag Melan-A/MART-1. Ex vivo analysis revealed three Ag-specific effector memory (EM) populations, as follows: CD28-negative EM (EM28–) T cells strongly expressing granzyme/perforin, and two EM28+ subsets, one with high and the other with low level expression of these cytotoxic proteins. For further functional characterization, we generated 117 stable CD8 T cell clones by ex vivo flow cytometry-based sorting of these subsets. All EM28–-derived clones lysed target cells with high efficacy. In contrast, EM28+-derived clones were heterogenous, and could be classified in two groups, one with high and the other with low killing capacity, correlating with granzyme/perforin expression. High and low killer phenotypes remained surprisingly stable for several months. However, strongly increased granzyme expression and cytotoxicity were observed after exposure to IL-12. Thus, the data reveal a newly identified subset of CD28+ conditional killer T cells. Because CD28 can mediate strong costimulatory signals, tight cytotoxicity control, as shown in this study through IL-12, may be particularly important for subsets of T cells expressing CD28.
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 study was sponsored and supported by the Ludwig Institute for Cancer Research, the Cancer Research Institute (New York), the Swiss Cancer League/Oncosuisse Grant 01323-02-2003, the Emma Muschamp Foundation, the Swiss National Science Foundation Grant 3200B0-107693, and the Swiss National Center of Competence in Research Molecular Oncology.
2 C.B., P.B., N.R., and D.E.S. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Daniel E. Speiser, Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Hôpital Orthopédique, Niveau 5 Est, Avenue Pierre-Decker 4, CH-1005 Lausanne, Switzerland. E-mail address: daniel.speiser{at}hospvd.ch
4 Abbreviations used in this paper: EM, effector memory; DC, dendritic cell; Melan-A, melanoma Ag-A.
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