HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Saether, P. C. Articles by Dissen, E. Search for Related Content PubMed PubMed Citation Articles by Saether, P. C. Articles by Dissen, E.

KLRE/I1 and KLRE/I2: A Novel Pair of Heterodimeric Receptors That Inversely Regulate NK Cell Cytotoxicity¹

Per C. Saether^2,*, Ingunn H. Westgaard^*, Sigurd E. Hoelsbrekken^*, Jonathan Benjamin, Lewis L. Lanier, Sigbjørn Fossum^* and Erik Dissen^*

^* Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; and Department of Microbiology and Immunology and the Cancer Research Institute, University of California San Francisco, San Francisco, CA 94143

NK cells identify infected, neoplastic, or MHC-disparate target cells via several different receptors. The NK cell receptor KLRE1 lacks known signaling motifs but has nevertheless been shown to regulate NK cell-mediated cytotoxicity. Here we demonstrate that KLRE1 forms functional heterodimers with either KLRI1 or KLRI2. Cotransfection with KLRE1 was necessary for surface expression of the NK cell receptor chains KLRI1 and KLRI2 in 293T cells. Moreover, KLRE1 can be coimmunoprecipitated with KLRI1 or KLRI2 from transfected NK cell lines. By flow cytometry, KLRE1 and KLRI1 showed colinear expression on NK cells, suggesting surface expression as heterodimers. Unlike other killer cell lectin-like receptors, KLRE1/KLRI1 and KLRE1/KLRI2 heterodimers predominantly migrated as single chains in SDS-PAGE, indicating noncovalent association. KLRI1 was coimmunoprecipitated with the tyrosine phosphatase Src homology region 2 domain-containing phosphatase 1. In accordance with an inhibitory function, anti-HA Ab induced reduced killing of FcR-bearing targets by KLRI1-HA-transfected NK cell lines in a redirected cytotoxicity assay. Reciprocally, KLRI2-HA transfectants displayed increased killing in this assay. Finally, Ab to KLRE1 induced inhibition in KLRI1-transfected cells but increased cytotoxicity in KLRI2 transfectants, demonstrating that KLRE/I1 is a functional inhibitory heterodimer in NK cells, whereas KLRE/I2 is an activating heterodimeric receptor.

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 Research Council of Norway, the Norwegian Cancer Society, Bergljot and Sigurd Skaugen’s fund, Anders Jahre’s fund, and National Institutes of Health Grant AI068129. L.L.L. is an American Cancer Society Research Professor.

² Address correspondence and reprint requests to Dr. Per C. Saether, Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1105 Blindern, 0317 Oslo, Norway. E-mail address: p.c.sather{at}medisin.uio.no

³ Abbreviations used in this paper: SHP-1, Src homology region 2 domain-containing phosphatase 1; KLR, killer cell lectin-like receptor; PVDF, polyvinylidene difluoride.