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,#,,**
* Department of Clinical Immunology, German Rheumatism Research Centre, Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany;
Istituto Giannina Gaslini, Largo Gaslini, Genoa, Italy;
Department of Human Pathology, School of Medicine, University of Messina, Messina, Italy;
Ospedale Santi Antonio Biagio Cesare Arrigo, Alessandria, Italy;
¶ Istituto Nazionale Ricerca sul Cancro, Genoa, Italy;
|| Ospedale Santa Croce e Carle, Cuneo, Italy;
# Department of Experimental Medicine, University of Genova, Genova, Italy;
** Laboratory of Viral Immunobiology, and Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021; and
Centro di Eccellenza Ricerca Biomedica, University of Genova, Genova, Italy
Human NK cells can be divided into CD56dimCD16+ killer Ig-like receptors (KIR)+/– and CD56brightCD16– KIR– subsets that have been characterized extensively regarding their different functions, phenotype, and tissue localization. Nonetheless, the developmental relationship between these two NK cell subsets remains controversial. We report that, upon cytokine activation, peripheral blood (PB)-CD56bright NK cells mainly gain the signature of CD56dim NK cells. Remarkably, KIR can be induced not only on CD56bright, but also on CD56dim KIR– NK cells, and their expression correlates with lower proliferative response. In addition, we demonstrate for the first time that PB-CD56dim display shorter telomeres than PB- and lymph node (LN)-derived CD56bright NK cells. Along this line, although human NK cells collected from nonreactive LN display almost no KIR and CD16 expression, NK cells derived from highly reactive LN, efferent lymph, and PB express significant amounts of KIR and CD16, implying that CD56bright NK cells could acquire these molecules in the LN during inflammation and then circulate through the efferent lymph into PB as KIR+CD16+ NK cells. Altogether, our results suggest that CD56brightCD16– KIR– and CD56dimCD16+KIR+/– NK cells correspond to sequential steps of differentiation and support the hypothesis that secondary lymphoid organs can be sites of NK cell final maturation and self-tolerance acquisition during immune reaction.
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 funded by grants from Associazione Italiana Ricerca sul Cancro and from Comitato Interministeriale per la Programmazione Economica (02/07/2004, Centro di Biotecnologie Avanzate Project) (to G.Fe.). C.R. is supported by a European Molecular Biology Organization long-term fellowship. B.M. is supported by a fellowship from Fondazione Italiana Ricerca sul Cancro. C.M. is supported by the National Cancer Institute (RO1CA108609).
2 Address correspondence and reprint requests to Dr. Guido Ferlazzo, Department of Human Pathology, School of Medicine, University of Messina Via Consolare Valeria, 98125 Messina, Italy; E-mail address: guido.ferlazzo{at}unime.it or Dr. Chiara Romagnani, Clinical Immunology, German Rheumatism Research Centre, Deutsches Rheuma-Forschungszentrum Berlin, Schumannstrasse 21/22, 10117 Berlin, Germany; E-mail address: romagnani{at}drfz.de
3 Abbreviations used in this paper: PB, peripheral blood; DC, dendritic cell; FISH, fluorescence in situ hybridization; KIR, killer Ig-like receptor; LN, lymph node; MFI, mean fluorescence intensity; ORF, open reading frame; PNA, peptide nucleic acid; RTL, relative telomere length; SLO, secondary lymphoid organ.
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