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Dominant Human CD8 T Cell Clonotypes Persist Simultaneously as Memory and Effector Cells in Memory Phase¹

Cédric Touvrey^*, Laurent Derré^*, Estelle Devevre^*, Patricia Corthesy, Pedro Romero^*, Nathalie Rufer and Daniel E. Speiser^2,*

^* Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne, Switzerland; and Multidisciplinary Oncology Center, Lausanne University Hospital (Centre Hospitalier Universitaire Vaudois), Switzerland

The adaptive immune system plays a critical role in protection at the time of secondary infection. It does so through the rapid and robust reactivation of memory T cells which are maintained long-term, in a phenotypically heterogeneous state, following their primary encounter with Ag. Although most HLA-A*0201/influenza matrix protein_58–66-specific CD8 T cells from healthy donors display characteristics typical of memory T cells, through our extensive phenotypic analysis we have further shown that up to 20% of these cells express neither the IL-7 receptor CD127 nor the costimulatory molecule CD28. In contrast to the majority of CD28^pos cells, granzyme B and perforin were frequently expressed by the CD28^neg cells, suggesting that they are effector cells. Indeed, these cells were able to kill target cells, in an Ag-specific manner, directly ex vivo. Thus, our findings demonstrate the remarkable long-term persistence in healthy humans of not only influenza-specific memory cells, but also of effector T cells. We further observed that granzyme B expression in influenza-specific CD8 T cells paralleled levels in the total CD8 T cell population, suggestive of Ag-nonspecific bystander activation. Sequencing of TCR - and β-chains showed that the TCR repertoire specific for this epitope was dominated by one, or a few, T cell clonotype per healthy donor. Moreover, our sequencing analysis revealed, for the first time in humans, that identical clonotypes can coexist as both memory and effector T cells, thereby supporting the principle of multipotent clonotypic differentiation.

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, the Swiss Cancer League/Oncosuisse, the Cancer Research Institute, and the Cancer Vaccine Collaborative.

² Address correspondence and reprint requests to Dr. Daniel Speiser, Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Hôpital Orthopédique, Niveau 5 Est, Avenue Pierre-Decker 4, CH-1011 Lausanne, Switzerland. E-mail address: daniel.speiser{at}hospvd.ch

³ Abbreviations used in this paper: pMHC, peptide MHC; CM, central memory; EM, effector memory; EMRA, effector; Flu-MA, influenza matrix; rev, reverse; KLRG1, killer cell lectin-like receptor G1; PD-1, programmed death 1.