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A New Subset of Human Naive CD8⁺ T Cells Defined by Low Expression of IL-7R¹

Nuno L. Alves^2,3,*, Ester M. M. van Leeuwen^2,4,*,, Ester B. M. Remmerswaal^*, Nienke Vrisekoop, Kiki Tesselaar, Eddy Roosnek, Ineke J. M. ten Berge^*, and René A. W. van Lier^5,*

^* Department of Experimental Immunology, Department of Internal Medicine, Division of Nephrology, Academic Medical Center, Amsterdam, The Netherlands, Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands; and Department of Internal Medicine, Division of Hematology, Geneva University Hospital, Geneva, Switzerland

Concomitant with an increased number of memory-type cells, the amount of naive T cells steadily declines with age. Although the regulatory mechanisms behind this conversion are not fully understood, the suggestion is that both alterations in thymic output and homeostatic signals mold the naive T cell pool. In this study, we identify a new subset of circulating CD27^highCD45RA^high CD8⁺ T cells characterized by low IL-7R message and protein expression. Analysis of TCR repertoire and TCR excision circle content together with ex vivo recovery of IL-7R expression indicated that these cells should be placed into the naive T cell pool. Compared with conventional IL-7R^high naive T cells, this subset displayed significantly lower levels of CD28 and higher levels of HLA-DR. Proliferative responses to anti-CD3/CD28 mAbs were indistinguishable from conventional naive T cells, but the responsiveness to IL-7 was limited. Strikingly, IL-7R^low naive T cells were particularly increased in circumstances of naive CD8⁺ T cells shortage, as in the elderly, in patients early after hemopoietic stem cell transplantation, and in HIV-infected individuals. As common chain cytokines induce rapid down-regulation of IL-7R, we propose that this new subset of naive T cells may encompass cells that have recently received homeostatic signals.

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 funded by a VICI Project grant and Research Grant 912-04-032 both from the Netherlands Organization for Scientific Research (to R.A.W.v.L.).

² N.L.A. and E.M.M.v.L. contributed equally to this work.

³ Current address: Unite des Cytokines et Developpment Lymphoide, Institut Pasteur, Paris, France.

⁴ Current address: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92092.

⁵ Address correspondence and reprint requests to Dr. René A. W. van Lier, Academic Medical Center, Laboratory for Experimental Immunology, K0-146, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail address: r.vanlier{at}amc.uva.nl

⁶ Abbreviations used in this paper: _c, common chain; TREC, TCR excision circle; HSCT, hemopoietic stem cell transplantation; RT-MLPA, reverse transcriptase multiplex ligation-dependent probe amplification.