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Clonotype Selection and Composition of Human CD8 T Cells Specific for Persistent Herpes Viruses Varies with Differentiation but Is Stable Over Time¹

Emanuela M. Iancu^*, Patricia Corthesy^*, Petra Baumgaertner, Estelle Devevre, Verena Voelter^*, Pedro Romero, Daniel E. Speiser and Nathalie Rufer^2,*,

^* Division of Experimental Oncology, Multidisciplinary Oncology Center, and Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne University Hospital, Lausanne, Switzerland

Protection from reactivation of persistent herpes virus infection is mediated by Ag-specific CD8 T cell responses, which are highly regulated by still poorly understood mechanisms. In this study, we analyzed differentiation and clonotypic dynamics of EBV- and CMV-specific T cells from healthy adults. Although these T lymphocytes included all subsets, from early-differentiated (EM/CD28^pos) to late-differentiated (EMRA/CD28^neg) stages, they varied in the sizes/proportions of these subsets. In-depth clonal composition analyses revealed TCR repertoires, which were highly restricted for CMV- and relatively diverse for EBV-specific cells. Virtually all virus-specific clonotypes identified in the EMRA/CD28^neg subset were also found within the pool of less differentiated "memory" cells. However, striking differences in the patterns of dominance were observed among these subsets, because some clonotypes were selected with differentiation while others were not. Late-differentiated CMV-specific clonotypes were mostly characterized by TCR with lower dependency on CD8 coreceptor interaction. Yet all clonotypes displayed similar functional avidities, suggesting a compensatory role of CD8 in the clonotypes of lower TCR avidity. Importantly, clonotype selection and composition of each virus-specific subset upon differentiation was highly preserved over time, with the presence of the same dominant clonotypes at specific differentiation stages within a period of 4 years. Remarkably, clonotypic distribution was stable not only in late-differentiated but also in less-differentiated T cell subsets. Thus, T cell clonotypes segregate with differentiation, but the clonal composition once established is kept constant for at least several years. These findings reveal novel features of the highly sophisticated control of steady state protective T cell activity in healthy adults.

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 Swiss National Center of Competence in Research Molecular Oncology, the Ludwig Institute for Cancer Research, and the Swiss National Science Foundation Grants 3100A0-105929 and 3200B0-118123. P.R. was funded in part by the FP6 European Union grant "Cancer Immunotherapy."

² Address correspondence and reprint requests to Dr. Nathalie Rufer, Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Hôpital Orthopédique, niv 5, Aile Est, Avenue Pierre-Decker 4, CH-1011 Lausanne, Switzerland. E-mail address: Nathalie.Rufer{at}unil.ch

³ Abbreviations used in this paper: CM, central-memory; EM, effector-memory; EMRA, effector-memory and effector.

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The JI 2009 183: 1-2. [Full Text]