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CD56^bright Human NK Cells Differentiate into CD56^dim Cells: Role of Contact with Peripheral Fibroblasts

Antoni Chan^1,*, Deng-Li Hong, Ann Atzberger, Simon Kollnberger^*, Andrew D. Filer, Christopher D. Buckley, Andrew McMichael^*, Tariq Enver and Paul Bowness^*

^* Medical Research Council Human Immunology Unit, and Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom; and Division of Immunity and Infection, Medical Research Council, Centre for Immune Regulation, University of Birmingham, Birmingham, United Kingdom

Human NK cells are divided into CD56^brightCD16^– cells and CD56^dimCD16⁺ cells. We tested the hypothesis that CD56^bright NK cells can differentiate into CD56^dim cells by prospectively isolating and culturing each NK subset in vitro and in vivo. Our results show that CD56^bright cells can differentiate into CD56^dim both in vitro, in the presence of synovial fibroblasts, and in vivo, upon transfer into NOD-SCID mice. In vitro, this differentiation was inhibited by fibroblast growth factor receptor-1 Ab, demonstrating a role of the CD56 and fibroblast growth factor receptor-1 interaction in this process. Differentiated CD56^dim cells had reduced IFN- production but increased perforin expression and cytolysis of cell line K562 targets. Flow cytometric fluorescent in situ hybridization demonstrated that CD56^bright NK cells had longer telomere length compared with CD56^dim NK cells, implying the former are less mature. Our data support a linear differentiation model of human NK development in which immature CD56^bright NK cells can differentiate into CD56^dim cells.

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 Address correspondence and reprint requests to Dr. Antoni Chan, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, U.K. E-mail address: achan{at}hammer.imm.ox.ac.uk

² Abbreviations used in this paper: NCAM, neural cell adhesion molecule; FGFR, fibroblast growth factor receptor; PNA, peptide nucleic acid; KIR, killer Ig-related receptor; FLS, fibroblast-like synoviocyte; CD62L, CD62 ligand.

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