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Rapid CD8⁺ T Cell Repertoire Focusing and Selection of High-Affinity Clones into Memory Following Primary Infection with a Persistent Human Virus: Human Cytomegalovirus¹

Elizabeth K. Day^*, Andrew J. Carmichael^*, Ineke J. M. ten Berge, Edward C. P. Waller^*, J. G. Patrick Sissons^* and Mark R. Wills^2,*

^* Department of Medicine, School of Clinical Medicine, Cambridge, United Kingdom; and Renal Transplant Unit, Division of Nephrology, Department of Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands

To investigate the mechanism of selection of individual human CD8⁺ T cell clones into long-term memory following primary infection with a persistent human virus (human CMV (HCMV)), we undertook a longitudinal analysis of the diversity of T cell clones directed toward an immunodominant viral epitope: we followed this longitudinally from early T cell expansion through the contraction phase and selection into the memory pool. We show that following initial HCMV infection, the early primary response against a defined epitope was composed of diverse clones possessing many different TCR Vβ segments. Longitudinal analysis showed that this usage rapidly focused predominantly on a single TCR Vβ segment within which dominant clones frequently had public TCR usage, in contrast to subdominant or contracted clones. Longitudinal clonotypic analysis showed evidence of disproportionate contraction of certain clones that were abundant in the primary response, and late expansion of clones that were subdominant in the primary response. All dominant clones selected into memory showed similar high functional avidity of their TCR, whereas two clones that greatly contracted showed substantially lower avidity. Expression of the IL-7R is required for survival of murine effector CD8⁺ T cells into memory, but in primary HCMV infection IL-7R was not detected on circulating Ag-specific cells until memory had been established. Thus, the oligoclonal T cell repertoire against an immunodominant persistent viral epitope is established early in primary infection by the rapid selection of public clonotypes, rather than being a stochastic process.

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 supported by the Wellcome Trust and Medical Research Council.

² Address correspondence and reprint requests to Dr. Mark R. Wills, Department of Medicine, Level 5, Addenbrookes Hospital, Hills Road, Cambridge, CB2 2QQ, United Kingdom. E-mail address: mrw1004{at}cam.ac.uk

³ Abbreviations used in this paper: HCMV, human CMV; LCL, lymphoblastoid cell line; PCC, pigeon cytochrome C.

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