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KIR Polymorphism Modulates the Size of the Adaptive NK Cell Pool in Human C Ytomegalovirus−Infected Individuals

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KIR Polymorphism Modulates the Size of the Adaptive NK Cell Pool in Human C Ytomegalovirus−Infected Individuals KIR Polymorphism Modulates the Size of the Adaptive NK Cell Pool in Human C ytomegalovirus−Infected Individuals This information is current as Angela R. Manser, Nadine Scherenschlich, Christine Thöns, of September 26, 2021. Hartmut Hengel, Jörg Timm and Markus Uhrberg J Immunol published online 13 September 2019 http://www.jimmunol.org/content/early/2019/09/12/jimmun ol.1900423 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2019/09/12/jimmunol.190042 Material 3.DCSupplemental 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 by guest on September 26, 2021 *average 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 © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published September 13, 2019, doi:10.4049/jimmunol.1900423 The Journal of Immunology KIR Polymorphism Modulates the Size of the Adaptive NK Cell Pool in Human Cytomegalovirus–Infected Individuals Angela R. Manser,* Nadine Scherenschlich,* Christine Tho¨ns,† Hartmut Hengel,‡,x Jo¨rg Timm,† and Markus Uhrberg* Acute infection with human CMV (HCMV) induces the development of adaptive NKG2C+ NK cells. In some cases, large expansions of this subset, characterized by coexpression of HLA-C–specific KIR, are stably maintained during the life-long latent phase of infection. The factors that control these unusual expansions in vivo are currently unknown. In this study, the role of KIR polymorphism and expression in this process was analyzed. It is shown that strong NKG2C+ NK cell expansions are dominated by single KIR clones, whereas moderate expansions are frequently polyclonal (p < 0.0001). Importantly, the choice of KIR was not arbitrary but biased toward usage of HLA-C–specific KIR encoded by the centromeric part of group A (cenA) haplotypes. Consideration of KIR allelic variation and gene copy number revealed that the cenA effect was predominantly due to the Downloaded from HLA-C2–specific KIR2DL1 receptor; presence of KIR2DL1 on NKG2C+ NK cells led to significantly larger clonal expansions than the cenB-encoded KIR2DL2 (p = 0.002). Expansion of NKG2C+KIR2DL1+ NK cells was always accompanied by the cognate ligand HLA-C2. Moreover, in these donors the frequency of NKG2C+ NK cells correlated with the concentration of anti-HCMV IgG (r = 0.62, p = 0.008), suggesting direct relevance of NKG2C+KIR2DL1+ NK cells for virus control. Altogether, the study suggests that the homeostasis of NKG2C+ NK cells in HCMV infection is at least partly controlled by coexpression of cognate inhibitory KIR. In particular, the strong interaction of KIR2DL1 and HLA-C2 ligands seems to promote large and stable http://www.jimmunol.org/ expansion of adaptive NK cells in HCMV infection. The Journal of Immunology, 2019, 203: 000–000. hallmark of NK cells is the expression of HLA class haplotypes represent combinations of conserved centromeric and I–specific inhibitory receptors. They constitute an im- telomeric gene blocks separated by a unique region constituting a A portant detection system for virally infected and ma- hotspot of recombination (4–6). The most common haplotype is lignantly transformed cells, which tend to downregulate HLA referred to as A haplotype and encodes inhibitory KIR for all three class I to escape adaptive immune responses (1) and at the same major HLA class I–encoded epitopes: on the centromeric part time mediate NK cell tolerance toward healthy cells. Two receptor KIR2DL1 and KIR2DL3, which are specific for the HLA-C2 and -C1 families are key to this system: the Ig-like killer cell Ig-like re- epitopes, respectively, and on the telomeric part the HLA-Bw4– by guest on September 26, 2021 ceptor (KIR) genes on human chromosome 19 and the lectin-like specific KIR3DL1. All non-A haplotypes are referred to as group B CD94 and NKG2 genes on chromosome 12. To detect even sub- haplotypes and are on the centromeric side characterized by lack tle changes in expression of single HLA class I or combinations or attenuation of the C2-specific KIR2DL1 receptor. Instead, thereof on aberrant cells, the members of these two receptor group B haplotypes encode the KIR2DL2 receptor that recognizes families are expressed in a clonally distributed fashion, leading to C1 as well as C2, albeit the latter with less avidity than KIR2DL1. the formation of complex NK cell repertoires (2). Importantly, KIR Another major difference between group A and B haplotypes genes are highly polymorphic, and besides allelic polymorphisms pertains to the possession of stimulatory KIR genes; group A hap- also exhibit extensive haplotypic diversity (3). The common KIR lotypes possess only one stimulatory KIR gene, KIR2DS4,which is often a nonproductive allele, whereas group B haplotypes harbor up to five different stimulatory KIR genes (2, 3). *Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich Heine University, University Hospital of Du¨sseldorf, 40225 Du¨sseldorf, Germany; The CD94/NKG2A heterodimer represents the only inhibitory †Institute of Virology, Heinrich Heine University, University Hospital of Du¨sseldorf, receptor within the CD94/NKG2 family of lectin-like receptors and 40225 Du¨sseldorf, Germany; ‡Institute of Virology, University Medical Center, x is also the evolutionary most conserved HLA class I–specific in- Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; and Faculty of Medicine, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany hibitory receptor in primates. It interacts with the similarly con- ORCIDs: 0000-0002-3482-816X (H.H.); 0000-0001-7799-3045 (J.T.); 0000-0001- served HLA-E, which is an ubiquitously expressed nonclassical 9553-1987 (M.U.). HLA class I molecule that requires loading with leader peptides, Received for publication April 12, 2019. Accepted for publication August 14, 2019. predominantly from other HLA class I molecules, for expression This work was supported by the Deutsche Forschungsgemeinschaft (Research Grant on the cell surface (7–9). NKG2A plays a key role for tolerance UH91/7 to M.U. and HE2526/9-1 to H.H.) and by Infect-ERA Grant TANKACY induction of NK cells because it is the first class I–specific in- (BMBF 031L0090 to H.H.). hibitory receptor on the cell surface of developing NK cells and Address correspondence and reprint requests to Dr. Markus Uhrberg, Institute for mediates inhibition by all healthy body cells because of its Transplantation Diagnostics and Cell Therapeutics, Heinrich Heine University, Uni- versity Hospital of Du¨sseldorf, Building 14.80, Moorenstrasse 5, 40225 Du¨sseldorf, ubiquitously expressed ligand HLA-E. NKG2A expression thus Germany. E-mail address: [email protected] secures tolerance and enables full functionality of NK cells at a The online version of this article contains supplemental material. stage before the initiation of inhibitory KIR expression. The stim- Abbreviations used in this article: HCMV, human CMV; KIR, killer cell Ig-like ulatory NKG2C receptor, which like NKG2A is specific for HLA-E, receptor; MFI, mean fluorescence intensity; PCR-SSP, PCR with sequence-specific is expressed at a later developmental stage and preferentially found primer. on terminally differentiated NK cells (10). In mature NK cells, all Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 possible combinations of inhibitory and stimulatory NKG2 and www.jimmunol.org/cgi/doi/10.4049/jimmunol.1900423 2 KIR POLYMORPHISM MODULATES ADAPTIVE NK CELL EXPANSIONS KIR receptors are realized, leading to complex NK cell rep- Materials and Methods ertoires. In a given individual, these repertoires are stably Blood samples maintained over time, whereas they are highly variable be- PBMC were isolated from randomly selected buffy coats (n = 270; kindly tween individuals. provided by the DRK Blutspendedienst Baden-Wu¨rttemberg/Hessen, The exogenous factors that are involved in shaping NK cell Frankfurt a. M.) or whole blood donations from healthy volunteers (n =6) repertoires are only partly understood. In this regard, it became using density gradient centrifugation (Biocoll separating solution; Biochrom). recently clear that infection with human CMV (HCMV) can lead to Prior to PBMC isolation, serum was collected and stored at 220˚C. Cells dramatic changes in the composition of NK cell repertoires (11). were cryopreserved in RPMI 1640 (Lonza) containing 50% FBS (Biochrom) and 10% DMSO (Santa Cruz Biotechnology) and stored in liquid nitrogen. HCMV (human herpesvirus 5) is a member of the b-herpesvirus Samples were excluded from analyses (8/276) if ,1000 NK cells could be family that has coevolved with its host species to establish measured (because of poor sample quality after thawing, 5/276) or if no a commensal relationship that leads to life-long infection in HCMV serology could be determined (because of missing serum samples, most cases without clinical
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