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* Institute of Medical Microbiology and Hygiene, Department of Immunology, University of Freiburg, Germany;
Nanyang Technological University, Singapore; and
Institute of Pathology, Technical University, Munich, Germany
The killer cell lectin-like receptor G1 (KLRG1) is expressed by NK cells and memory T cells in man and mice. Cadherins were recently identified as ligands for mouse KLRG1 but ligands for human KLRG1 have not yet been defined. In this study, we first demonstrate that human E-cadherin is a ligand for human KLRG1. This finding is remarkable because human and mouse KLRG1 show only an intermediate degree of homology (57% aa identity). In addition, we show that E-cadherin, expressed on K562 target cells, inhibited polyclonal human NK cells. Inhibition of NK cell function was observed consistently in three independent functional assays but the extent of inhibition was modest and required high expression of E-cadherin on target cells. E-cadherin function is often inactivated during development of human carcinomas and splice-site mutations resulting in in-frame loss of exon 8 or 9 occur frequently in diffuse type gastric carcinomas. Our experiments further revealed that interaction of human KLRG1 to E-cadherin was susceptible to these tumor-associated mutations and that KLRG1+ NK cells were triggered more easily by K562 target cells carrying these mutations in comparison to target cells expressing wild-type E-cadherin. These results also indicate that the E-cadherin binding sites important for homophilic interaction are also involved in KLRG1 binding. Taken together, these data demonstrate that the main adhesion molecule of epithelial tissue, E-cadherin, is involved in regulation of NK cells in both humans and mice.
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 the Deutsche Forschungsgemeinschaft (SFB620, Teilprojekt B2).
2 S. S. and C. G. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Hanspeter Pircher, Institute of Medical Microbiology and Hygiene, Hermann-Herder-Strasse 11, Freiburg, Germany. E-mail address: hanspeter.pircher{at}uniklinik-freiburg.de
4 Abbreviations used in this paper: KLRG1, killer cell lectin-like receptor G1; MF, mean fluorescence; int, intermediate.
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