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International Immunology Advance Access originally published online on February 27, 2008
International Immunology 2008 20(4):555-563; doi:10.1093/intimm/dxn013
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

KIR2DS1-mediated activation overrides NKG2A-mediated inhibition in HLA-C C2-negative individuals

Bree Foley1,2, Dianne De Santis1,2, Louise Lathbury1,2, Frank Christiansen1,2 and Campbell Witt1

1 Department of Clinical Immunology and Immunogenetics, PathWest Laboratory Medicine, Royal Perth Hospital, Perth, Western Australia, Australia
2 Department of Surgery and Pathology, University of Western Australia, Perth, Western Australia, Australia

Correspondence to: C. Witt; E-mail: Campbell.Witt{at}health.wa.gov.au

NK cell cytotoxicity is controlled through a balance of both activating and inhibitory signals. The HLA specificity of alloreactive NK cells has been previously shown to be controlled by inhibitory killer immunoglobulin-like receptors (KIRs). Alloreactive NK cells lyse targets that lack the HLA ligand for their inhibitory KIR. We have characterized in detail an alloreactive NK clone in which the specificity is controlled by an activating receptor, KIR2DS1. Only target cells expressing the HLA-C group 2 (C2) epitope were lysed by this clone and homozygous C2 targets were lysed more strongly than heterozygous C1/C2 targets. Anti-CD158a (KIR2DS1) blocked lysis of targets confirming KIR2DS1 was responsible. Although this NK clone expressed NKG2A, an inhibitory receptor whose ligand is HLA-E, targets with ligands for both KIR2DS1 and NKG2A were lysed by this clone indicating that the KIR2DS1-mediated activation signal overrides the NKG2A-mediated inhibitory signal. KIR2DS1 activated NK clones in polyclonally expanded NK cultures from a donor that lacked the C2 epitope accounted for ~1% of all NK cells. This study highlights a potential role for NK cells controlled by activating KIR in mediating NK alloreactivity.

Keywords: activating receptor, alloreactivity, KIR, NK cell

Transmitting editor: E. Vivier

Received 20 November 2007, accepted 23 January 2008.


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