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KIR3DL1/S1 Receptor on Human NK Cells Functional Polymorphism Of Functional Polymorphism of the KIR3DL1/S1 Receptor on Human NK Cells Geraldine M. O'Connor, Kieran J. Guinan, Rodat T. Cunningham, Derek Middleton, Peter Parham and Clair M. This information is current as Gardiner of October 2, 2021. J Immunol 2007; 178:235-241; ; doi: 10.4049/jimmunol.178.1.235 http://www.jimmunol.org/content/178/1/235 Downloaded from References This article cites 28 articles, 10 of which you can access for free at: http://www.jimmunol.org/content/178/1/235.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 2, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Functional Polymorphism of the KIR3DL1/S1 Receptor on Human NK Cells1 Geraldine M. O’Connor,* Kieran J. Guinan,* Rodat T. Cunningham,† Derek Middleton,† Peter Parham,‡ and Clair M. Gardiner2* NK cells express both inhibitory and activatory receptors that allow them to recognize target cells through HLA class I Ag expression. KIR3DL1 is a receptor that recognizes the HLA-Bw4 public epitope of HLA-B alleles. We demonstrate that poly- morphism within the KIR3DL1 receptor has functional consequences in terms of NK cell recognition of target. Inhibitory alleles of KIR3DL1 differ in their ability to recognize HLA-Bw4 ligand, and a consistent hierarchy of ligand reactivity can be defined. KIR3DS1, which segregates as an allele of KIR3DL1, has a short cytoplasmic tail characteristic of activatory receptors. Because it is very similar to KIR3DL1 in the extracellular domains, it has been assumed that KIR3DS1 will recognize a HLA-Bw4 ligand. In this study, we demonstrate that KIR3DS1 is expressed as a protein at the cell surface of NK cells, where it is recognized by the Downloaded from Z27 Ab. Using this Ab, we found that KIR3DS1 is expressed on a higher percentage of NK cells in KIR3DS1 homozygous compared with heterozygous donors. In contrast to the inhibitory KIR3DL1 allotypes, KIR3DS1 did not recognize HLA-Bw4 on EBV- transformed cell lines. The Journal of Immunology, 2007, 178: 235–241. atural killer cells are cytotoxic lymphocytes of the innate alleles have the Bw4 epitope that is recognized by the KIR3DL1 immune system that are particularly important in the (3DL1) receptor on NK cells (10). Although highly conserved, N control of viral infections (1, 2). NK cells express a there is some limited variability within the Bw4 epitope and at http://www.jimmunol.org/ range of activatory and inhibitory cell surface receptors, and their least four different amino acid sequences are known (11). This responses are controlled by the overall balance of positive and diversity has the potential to influence NK cell recognition negative signals received (3, 4). Cell activation can result from through 3DL1. either increased activatory or decreased inhibitory signaling inputs. KIR genes are characterized by diversity at many levels includ- An important source of inhibitory signals comes from HLA- ing polygeny, polymorphism, and expression characteristics (5). specific receptors, including members of the killer cell Ig-like This is a reflection of their recent and rapid evolution (12). We 3 receptor (KIR) family and the CD94/NKG2a heterodimer (5, hypothesized that given the strong pressure on KIR to diversify, 6). When HLA expression is altered during viral infection or polymorphism present in individual genes would have functional by guest on October 2, 2021 during transformation, this inhibitory signal is disrupted; NK consequences within the human immune system. As our prototype cells thus become activated and can mediate cytotoxicity gene we investigated 3DL1, which we have previously shown to against the target cell. be highly polymorphic (13). Most of the alleles of the 3DL1 HLA class I genes are highly polymorphic, and most of the locus encode for inhibitory receptors, of which 3DL1*001 and ␣ variability resides in the Ag-binding groove comprised of the 1 3DL1*002 are the most common (13). We therefore chose these ␣ and 2 domains of the H chain (6, 7). This variability affects the receptors for investigation along with the distinctive KIR3SD1 peptide that can bind and therefore influences recognition of Ag by (3DS1) allele. the immune system (8). To cope with diversity inherent in HLA, 3DS1 is present in ϳ38% of the population (14). It is highly NK cell receptors target relatively conserved epitopes within HLA. homologous to 3DL1 in its extracellular domains (ECD) but re- HLA-B alleles are characterized by having either a Bw4 or a Bw6 sembles activatory KIR in the intracellular portion of the molecule. epitope at residues 77–84 of the ␣1 H chain (9). Although there is Activatory KIR have no inherent signaling capacity because they no known receptor for Bw6, approximately one-third of HLA-B have a truncated cytoplasmic tail (5). However, upon receptor li- gation, they can recruit positive signaling adaptor molecules that result in NK cell activation (15–17). No serological reagents for *School of Biochemistry and Immunology, Trinity College, Dublin, Ireland; †North- ern Ireland Histocompatibility and Immunogenetics Laboratory, Belfast City Hospi- 3DS1 have been described to date, and this has hampered bio- tal, Belfast, Northern Ireland; and ‡Department of Structural Biology, Stanford Uni- chemical and functional characterization of this receptor. 3DS1 is versity, Stanford, CA 94305 of particular interest because it has been reported that, in combi- Received for publication May 31, 2006. Accepted for publication October 4, 2006. nation with HLA-Bw4 molecules with isoleucine at position 80 The costs of publication of this article were defrayed in part by the payment of page (Bw4–80Ile), its expression is associated with delayed progres- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. sion to AIDS (17). This association was only seen in the presence 1 This work was supported by an Irish Health Research Board Project grant. of both 3DS1 and Bw4–80Ile, suggesting that in these patients, 2 these receptors interact functionally. One attractive hypothesis is Address correspondence and reprint requests to Dr. Clair Gardiner, School of Bio- ϩ chemistry and Immunology, Trinity College, Dublin 2, Ireland. E-mail address: that 3DS1 NK cells recognize and kill HLA Bw4–80Ile HIV- [email protected] infected targets, allowing control of infection. Due to the very high 3 Abbreviations used in this paper: KIR, killer cell Ig-like receptor; ECD, extracellular degree of similarity to 3DL1 extracellularly, 3DS1 is expected to domain; LILR, leukocyte Ig-like receptor; F, forward; R, reverse. have similar ligand specificity, but neither this nor definitive cell Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$2.00 surface expression have been demonstrated. www.jimmunol.org 236 FUNCTIONAL POLYMORPHISM OF KIR3DL1/S1 RECEPTOR In this study, we demonstrate that polymorphism within 3DL1 influences recognition by the HLA-Bw4 epitope and, in turn, poly- morphism within HLA-B contributes to altered recognition of 3DL1. In addition, we demonstrate that 3DS1 is expressed at the cell surface, where it is recognized by the Z27 Ab. However, despite a significant genetic association with delayed disease progression in HIV-infected patients (17), we did not detect any functional interaction between 3DS1 and HLA-Bw4. Materials and Methods Cell culture The T cell line Jurkat, the MHC class I-deficient EBV-transformed B cell line 721.221, and its transfectants 721.221B*0702, 721.221B*2705, 721.221B*3801, 721.221B*5101, and 721.221B*5801 (10) were main- tained in RPMI 1640 medium (Invitrogen Life Technologies) supple- mented with 10% FCS (PAA Laboratories). Transfectants with similar levels of protein expression were used in experiments. Generation of NK cell cultures Blood samples were drawn from normal healthy individuals from whom Downloaded from written consent was obtained. PBMCs were isolated using Lymhoprep (Axis-Shield) gradient. DNA was isolated using Wizard Genomic DNA isolation kit (Promega), and 3DL1 allelic typing analysis was performed as described previously (13). NK cells were isolated by magnetic bead iso- lation using NK Isolation kit II (Miltenyi Biotec) according to the manu- FIGURE 1. Variability in HLA-Bw4 affects recognition by 3DL1*001. facturer’s instructions. NK cells were stained with anti-CD56FITC Ab (BD A, 3DL1*001ECD Jurkat cells were transfected with a NFAT-luciferase Biosciences), anti-3DL1PE Ab (Beckman Coulter), and anti-CD3PerCP reporter plasmid. Cells were then stimulated with the 721.221 cell line and http://www.jimmunol.org/ Ab (BD Biosciences), and CD56-positive, CD3-negative, 3DL1-positive a panel of its HLA transfectants at a stimulator:responder ratio of 1:5. cells were sorted on a BD FACS Aria (BD Biosciences). Polyclonal cul- tures were maintained in CellGro medium (CellGenix) supplemented with Firefly luciferase activity was measured after 18 h as a readout of NFAT 5% human AB serum (Sigma-Aldrich), 200 U/ml human recombinant IL-2 activation and is expressed relative to unstimulated control. CD3/CD28 (Biological Resources Branch, National Cancer Institute), 50 ng/ml OKT3 Dynabeads (3 beads/cell) were used as a positive control.
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