KLRE/I1 and KLRE/I2: a novel pair of heterodimeric receptors that inversely regulate NK cell cytotoxicity.
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.
Saether
Per C
PC
Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. p.c.sather@medisin.uio.no
Westgaard
Ingunn H
IH
Hoelsbrekken
Sigurd E
SE
Benjamin
Jonathan
J
Lanier
Lewis L
LL
Fossum
Sigbjørn
S
Dissen
Erik
E
D000818:Animals; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D019281:Dimerization; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D051381:Rats; D011971:Receptors, Immunologic / Q000276:immunology* / Q000378:metabolism; D018039:Receptors, Tachykinin / Q000276:immunology* / Q000378:metabolism; D014162:Transfection
C499792:Klri1 protein, rat; C499794:Klri2 protein, rat; D037181:Lectins, C-Type; D011971:Receptors, Immunologic; D018039:Receptors, Tachykinin; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11