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In Vivo Persistence of Codominant Human CD8⁺ T Cell Clonotypes Is Not Limited by Replicative Senescence or Functional Alteration¹

Laurent Derré^2,*, Marc Bruyninx^2,*,, Petra Baumgaertner^*, Estelle Devevre^*, Patricia Corthesy, Cédric Touvrey^*, Yolanda D. Mahnke, Hanspeter Pircher, Verena Voelter^¶, Pedro Romero^*, Daniel E. Speiser^2,* and Nathalie Rufer^2,3,

^* Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, University Hospital of Lausanne, Lausanne, Switzerland; Swiss Institute for Experimental Cancer Research, Epalinges, Switzerland; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Institute for Medical Microbiology and Hygiene, Department of Immunology, University of Freiburg, Freiburg, Germany; and ^¶ Multidisciplinary Oncology Center, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland

T cell responses to viral epitopes are often composed of a small number of codominant clonotypes. In this study, we show that tumor Ag-specific T cells can behave similarly. In a melanoma patient with a long lasting HLA-A2/NY-ESO-1-specific T cell response, reaching 10% of circulating CD8 T cells, we identified nine codominant clonotypes characterized by individual TCRs. These clonotypes made up almost the entire pool of highly differentiated effector cells, but only a fraction of the small pool of less differentiated "memory" cells, suggesting that the latter serve to maintain effector cells. The different clonotypes displayed full effector function and expressed TCRs with similar functional avidity. Nevertheless, some clonotypes increased, whereas others declined in numbers over the observation period of 6 years. One clonotype disappeared from circulating blood, but without preceding critical telomere shortening. In turn, clonotypes with increasing frequency had accelerated telomere shortening, correlating with strong in vivo proliferation. Interestingly, the final prevalence of the different T cell clonotypes in circulation was anticipated in a metastatic lymph node withdrawn 2 years earlier, suggesting in vivo clonotype selection driven by metastases. Together, these data provide novel insight in long term in vivo persistence of T cell clonotypes associated with continued cell turnover but not replicative senescence or functional alteration.

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 (NCCR) Molecular Oncology, the Ludwig Institute for Cancer Research, the Cancer Research Institute, NY, the Swiss Cancer League/Oncosuisse Grant 01323-02-2003, and the Swiss National Science Foundation Grants 3200B0-107693 and 3100A0-105929.

² L.D., M.B., D.S., and N.R. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Nathalie Rufer, Swiss Institute for Experimental Cancer Research, 155 ch. des Boveresses, Epalinges, Switzerland. E-mail address: Nathalie.Rufer{at}isrec.ch

⁴ Abbreviations used in this paper: TILN, tumor-infiltrated lymph node cells; PD, programmed death; int, intermediate; EM, effector-memory; CM, central-memory.

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