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IL-12-Dependent Inducible Expression of the CD94/NKG2A Inhibitory Receptor Regulates CD94/NKG2C⁺ NK Cell Function¹

Andrea Sáez-Borderías^*, Neus Romo^*, Giuliana Magri^*, Mónica Gumá^2,*, Ana Angulo and Miguel López-Botet^3,*,

^* Molecular Immunopathology Unit, Universitat Pompeu Fabra, Barcelona, Spain; Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; and Institut Municipal d’Investigació Mèdica-Hospital del Mar, Barcelona, Spain

The inhibitory CD94/NKG2A and activating CD94/NKG2C killer lectin-like receptors specific for HLA-E have been reported to be selectively expressed by discrete NK and T cell subsets. In the present study, minor proportions of NK and T cells coexpressing both CD94/NKG2A and CD94/NKG2C were found in fresh peripheral blood from adult blood donors. Moreover, CD94/NKG2A surface expression was transiently detected upon in vitro stimulation of CD94/NKG2C⁺ NK cells in the presence of irradiated allogeneic PBMC or rIL-12. A similar effect was observed upon coculture of NKG2C⁺ NK clones with human CMV-infected autologous dendritic cell cultures, and it was prevented by an anti-IL-12 mAb. NKG2A inhibited the cytolytic activity of NKG2C⁺ NK clones upon engagement either by a specific mAb or upon interaction with a transfectant of the HLA class I-deficient 721.221 cell line expressing HLA-E. These data indicate that beyond its constitutive expression by an NK cell subset, NKG2A may be also transiently displayed by CD94/NKG2C⁺ NK cells under the influence of IL-12, providing a potential negative regulatory feedback mechanism.

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 Grants SAF2007-61814 to M.L.-B. (Ministerio de Ciencia e Innovación), MRTN-CT-2005-019248 (Marie Curie Training Network, European Union), Red Heracles (Instituto de Salud Carlos III), and SAF2005-05633 to A.A. (Ministerio de Ciencia y Tecnología). A.S.-B. is supported by a fellowship from Departament d’Universitats, Recerca i Societat de la Informació (Generalitat de Catalunya), N.R. is supported by a fellowship from Instituto de Salud Carlos III, and G.M. is supported by a Marie Curie Training Network (European Union).

² Current address: Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093.

³ Address correspondence and reprint requests to Dr. Miguel López-Botet, Universitat Pompeu Fabra, Doctor Aiguader 88, 08003 Barcelona, Spain. E-mail address: miguel.lopez-botet{at}upf.edu

⁴ Abbreviations used in this paper: NKR, natural killer cell receptors; DC, dendritic cells; HCMV, human CMV; KIR, killer Ig-like receptor; moDC, monocyte-derived DC.