• This record comes from PubMed

Activating NKG2C Receptor: Functional Characteristics and Current Strategies in Clinical Applications

. 2023 Mar 10 ; 71 (1) : 9. [epub] 20230310

Language English Country Poland Media electronic

Document type Journal Article, Review

Grant support
No. 2018/31/B/NZ2/03065 Narodowe Centrum Nauki

Links

PubMed 36899273
PubMed Central PMC10004456
DOI 10.1007/s00005-023-00674-z
PII: 10.1007/s00005-023-00674-z
Knihovny.cz E-resources

The interest in NK cells and their cytotoxic activity against tumour, infected or transformed cells continuously increases as they become a new efficient and off-the-shelf agents in immunotherapies. Their actions are balanced by a wide set of activating and inhibitory receptors, recognizing their complementary ligands on target cells. One of the most studied receptors is the activating CD94/NKG2C molecule, which is a member of the C-type lectin-like family. This review is intended to summarise latest research findings on the clinical relevance of NKG2C receptor and to examine its contribution to current and potential therapeutic strategies. It outlines functional characteristics and molecular features of CD94/NKG2C, its interactions with HLA-E molecule and presented antigens, pointing out a key role of this receptor in immunosurveillance, especially in the human cytomegalovirus infection. Additionally, the authors attempt to shed some light on receptor's unique interaction with its ligand which is shared with another receptor (CD94/NKG2A) with rather opposite properties.

See more in PubMed

Achour A, Baychelier F, Besson C, et al. Expansion of CMV-mediated NKG2C+ NK cells associates with the development of specific de novo malignancies in liver-transplanted patients. J Immunol. 2014;192:503–511. doi: 10.4049/jimmunol.1301951. PubMed DOI

Alsulami K, Bolastig N, Dupuy FP, et al. Influence of NKG2C genotypes on HIV susceptibility and viral load set point. J Virol. 2021;95:e0041721. doi: 10.1128/JVI.00417-21. PubMed DOI PMC

Asenjo J, Muntasell A, López-Botet M, et al. Complete genomic characterization of a new KLRC2 allele, NKG2C*03. HLA. 2021;98:259–261. doi: 10.1111/tan.14231. PubMed DOI PMC

Bachmayer N, Sohlberg E, Sundström Y, et al. Women with pre-eclampsia have an altered NKG2A and NKG2C receptor expression on peripheral blood natural killer cells. Am J Reprod Immunol. 2009;62:147–157. doi: 10.1111/j.1600-0897.2009.00724.x. PubMed DOI

Batista MD, Ho EL, Kuebler PJ, et al. Skewed distribution of natural killer cells in psoriasis skin lesions. Exp Dermatol. 2013;22:64–66. doi: 10.1111/exd.12060. PubMed DOI PMC

Behrendt CE, Rosenthal J, Bolotin E, et al. Donor and recipient CMV serostatus and outcome of pediatric allogeneic HSCT for acute leukemia in the era of CMV-preemptive therapy. Biol Blood Marrow Transplant. 2009;15:54–60. doi: 10.1016/j.bbmt.2008.10.023. PubMed DOI PMC

Bennabi M, Tarantino N, Gaman A, et al. Persistence of dysfunctional natural killer cells in adults with high-functioning autism spectrum disorders: stigma/consequence of unresolved early infectious events? Mol Autism. 2019;10:22. doi: 10.1186/s13229-019-0269-1. PubMed DOI PMC

Béziat V, Dalgard O, Asselah T, et al. CMV drives clonal expansion of NKG2C+ NK cells expressing self-specific KIRs in chronic hepatitis patients. Eur J Immunol. 2012;42:447–457. doi: 10.1002/eji.201141826. PubMed DOI

Béziat V, Liu LL, Malmberg JA, et al. NK cell responses to cytomegalovirus infection lead to stable imprints in the human KIR repertoire and involve activating KIRs. Blood. 2013;121:2678–2688. doi: 10.1182/blood-2012-10-459545. PubMed DOI PMC

Bigley AB, Rezvani K, Shah N, et al. Latent cytomegalovirus infection enhances anti-tumour cytotoxicity through accumulation of NKG2C+ NK cells in healthy humans. Clin Exp Immunol. 2016;185:239–251. doi: 10.1111/cei.12785. PubMed DOI PMC

Björkström NK, Lindgren T, Stoltz M, et al. Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus. J Exp Med. 2011;208:13–21. doi: 10.1084/jem.20100762. PubMed DOI PMC

Björkström NK, Svensson A, Malmberg KJ, et al. Characterization of natural killer cell phenotype and function during recurrent human HSV-2 infection. PLoS ONE. 2011;6:e27664. doi: 10.1371/journal.pone.0027664. PubMed DOI PMC

Bogunia-Kubik K, Łacina P. Non-KIR NK cell receptors: role in transplantation of allogeneic haematopoietic stem cells. Int J Immunogenet. 2021;48:157–171. doi: 10.1111/iji.12523. PubMed DOI

Brostjan C, Sobanov Y, Glienke J, et al. The NKG2 natural killer cell receptor family: comparative analysis of promoter sequences. Genes Immun. 2000;1:504–508. doi: 10.1038/sj.gene.6363715. PubMed DOI

Browne H, Smith G, Beck S, et al. A complex between the MHC class I homologue encoded by human cytomegalovirus and beta 2 microglobulin. Nature. 1990;347:770–772. doi: 10.1038/347770a0. PubMed DOI

Brunetta E, Fogli M, Varchetta S, et al. Chronic HIV-1 viremia reverses NKG2A/NKG2C ratio on natural killer cells in patients with human cytomegalovirus co-infection. AIDS. 2010;24:27–34. doi: 10.1097/QAD.0b013e3283328d1f. PubMed DOI

Bueno-Sánchez JC, Agudelo-Jaramillo B, Escobar-Aguilerae LF, et al. Cytokine production by non-stimulated peripheral blood NK cells and lymphocytes in early-onset severe pre-eclampsia without HELLP. J Reprod Immunol. 2013;97:223–231. doi: 10.1016/j.jri.2012.11.007. PubMed DOI

Calabrese DR, Chong T, Wang A, et al. NKG2C natural killer cells in bronchoalveolar lavage are associated with cytomegalovirus viremia and poor outcomes in lung allograft recipients. Transplantation. 2019;103:493–501. doi: 10.1097/TP.0000000000002450. PubMed DOI PMC

Cao K, Marin D, Sekine T, et al. Donor NKG2C copy number: an independent predictor for cmv reactivation after double cord blood transplantation. Front Immunol. 2018;9:2444. doi: 10.3389/fimmu.2018.02444. PubMed DOI PMC

Cauli A, Dessole G, Piga M, et al. Expression analysis of HLA-E and NKG2A and NKG2C receptors points at a role for natural killer function in ankylosing spondylitis. RMD Open. 2018;4:e000597. doi: 10.1136/rmdopen-2017-000597. PubMed DOI PMC

Chen C, Wang M, Zhu Z, et al. Multiple gene mutations identified in patients infected with influenza A (H7N9) virus. Sci Rep. 2016;6:25614. doi: 10.1038/srep25614. PubMed DOI PMC

Chiu E, Felices M, Cichocki F, et al. Anti-NKG2C/IL-15/anti-CD33 killer engager directs primary and iPSC-derived NKG2C+ NK cells to target myeloid leukemia. Mol Ther. 2021;29:3410–3421. doi: 10.1016/j.ymthe.2021.06.018. PubMed DOI PMC

Cichocki F, Cooley S, Davis Z, et al. CD56dimCD57+NKG2C+ NK cell expansion is associated with reduced leukemia relapse after reduced intensity HCT. Leukemia. 2016;30:456–463. doi: 10.1038/leu.2015.260. PubMed DOI PMC

Cichocki F, Valamehr B, Bjordahl R, et al. GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. Cancer Res. 2017;77:5664–5675. doi: 10.1158/0008-5472.CAN-17-0799. PubMed DOI PMC

Climent N, Ambrosioni J, González T, et al. Immunological and virological findings in a patient with exceptional post-treatment control: a case report. Lancet HIV. 2023;10:e42–e51. doi: 10.1016/S2352-3018(22)00302-2. PubMed DOI

Coupel S, Moreau A, Hamidou M, et al. Expression and release of soluble HLA-E is an immunoregulatory feature of endothelial cell activation. Blood. 2007;109:2806–2814. doi: 10.1182/blood-2006-06-030213. PubMed DOI

de Matos CT, Berg L, Michaëlsson J, et al. Activating and inhibitory receptors on synovial fluid natural killer cells of arthritis patients: role of CD94/NKG2A in control of cytokine secretion. Immunology. 2007;122:291–301. doi: 10.1111/j.1365-2567.2007.02638.x. PubMed DOI PMC

Della Chiesa M, Falco M, Podestà M, et al. Phenotypic and functional heterogeneity of human NK cells developing after umbilical cord blood transplantation: a role for human cytomegalovirus? Blood. 2012;119:399–410. doi: 10.1182/blood-2011-08-372003. PubMed DOI

Djaoud Z, Riou R, Gavlovsky PJ, et al. Cytomegalovirus-infected primary endothelial cells trigger NKG2C+ natural killer cells. J Innate Immun. 2016;8:374–385. doi: 10.1159/000445320. PubMed DOI PMC

Elmaagacli AH, Steckel NK, Koldehoff M, et al. Early human cytomegalovirus replication after transplantation is associated with a decreased relapse risk: evidence for a putative virus-versus-leukemia effect in acute myeloid leukemia patients. Blood. 2011;118:1402–1412. doi: 10.1182/blood-2010-08-304121. PubMed DOI

Fahnestock ML, Johnson JL, Feldman RM, et al. The MHC class I homolog encoded by human cytomegalovirus binds endogenous peptides. Immunity. 1995;3:583–590. doi: 10.1016/1074-7613(95)90129-9. PubMed DOI

Feyaerts D, van der Meer A, Joosten I, et al. Selective expansion and CMV-dependency in pregnancy trained human endometrial NK cells. Cell Mol Immunol. 2019;16:410–411. doi: 10.1038/s41423-018-0193-x. PubMed DOI PMC

Foley B, Cooley S, Verneris MR, et al. Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function. Blood. 2012;119:2665–2674. doi: 10.1182/blood-2011-10-386995. PubMed DOI PMC

Foley B, Cooley S, Verneris MR, et al. Human cytomegalovirus (CMV)-induced memory-like NKG2C(+) NK cells are transplantable and expand in vivo in response to recipient CMV antigen. J Immunol. 2012;189:5082–5088. doi: 10.4049/jimmunol.1201964. PubMed DOI PMC

Gamliel M, Goldman-Wohl D, Isaacson B, et al. Trained memory of human uterine NK cells enhances their function in subsequent pregnancies. Immunity. 2018;48:951–962.e5. doi: 10.1016/j.immuni.2018.03.030. PubMed DOI

Glienke J, Sobanov Y, Brostjan C, et al. The genomic organization of NKG2C, E, F, and D receptor genes in the human natural killer gene complex. Immunogenetics. 1998;48:163–173. doi: 10.1007/s002510050420. PubMed DOI

Goncalves A, Makalo P, Joof H, et al. Differential frequency of NKG2C/KLRC2 deletion in distinct African populations and susceptibility to trachoma: a new method for imputation of KLRC2 genotypes from SNP genotyping data. Hum Genet. 2016;135:939–951. doi: 10.1007/s00439-016-1694-2. PubMed DOI PMC

Goodier MR, Mela CM, Steel A, et al. NKG2C+ NK cells are enriched in AIDS patients with advanced-stage Kaposi's sarcoma. J Virol. 2007;81:430–433. doi: 10.1128/JVI.01567-06. PubMed DOI PMC

Goodier MR, White MJ, Darboe A, et al. Rapid NK cell differentiation in a population with near-universal human cytomegalovirus infection is attenuated by NKG2C deletions. Blood. 2014;124:2213–2222. doi: 10.1182/blood-2014-05-576124. PubMed DOI PMC

Grutza R, Moskorz W, Senff T, et al. NKG2Cpos NK cells regulate the expansion of cytomegalovirus-specific CD8 T cells. J Immunol. 2020;204:2910–2917. doi: 10.4049/jimmunol.1901281. PubMed DOI

Gumá M, Angulo A, Vilches C, et al. Imprint of human cytomegalovirus infection on the NK cell receptor repertoire. Blood. 2004;104:3664–3671. doi: 10.1182/blood-2004-05-2058. PubMed DOI

Gumá M, Busch LK, Salazar-Fontana LI, et al. The CD94/NKG2C killer lectin-like receptor constitutes an alternative activation pathway for a subset of CD8+ T cells. Eur J Immunol. 2005;35:2071–2080. doi: 10.1002/eji.200425843. PubMed DOI

Gumá M, Budt M, Sáez A, et al. Expansion of CD94/NKG2C+ NK cells in response to human cytomegalovirus-infected fibroblasts. Blood. 2006;107:3624–3631. doi: 10.1182/blood-2005-09-3682. PubMed DOI

Gumá M, Cabrera C, Erkizia I, et al. Human cytomegalovirus infection is associated with increased proportions of NK cells that express the CD94/NKG2C receptor in aviremic HIV-1-positive patients. J Infect Dis. 2006;194:38–41. doi: 10.1086/504719. PubMed DOI

Guo C, Wu M, Huang B, et al. Single-cell transcriptomics reveal a unique memory-like NK cell subset that accumulates with ageing and correlates with disease severity in COVID-19. Genome Med. 2022;14:46. doi: 10.1186/s13073-022-01049-3. PubMed DOI PMC

Guzmán-Fulgencio M, Berenguer J, Rallón N, et al. HLA-E variants are associated with sustained virological response in HIV/hepatitis C virus-coinfected patients on hepatitis C virus therapy. AIDS. 2013;27:1231–1238. doi: 10.1097/QAD.0b013e32835f5b9c. PubMed DOI

Gyurova IE, Ali A, Waggoner SN. Natural killer cell regulation of B cell responses in the context of viral infection. Viral Immunol. 2020;33:334–341. doi: 10.1089/vim.2019.0129. PubMed DOI PMC

Hammer Q, Rückert T, Borst E, et al. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. Nat Immunol. 2018;19:453–463. doi: 10.1038/s41590-018-0082-6. PubMed DOI

Hammer Q, Dunst J, Christ W, et al. SARS-CoV-2 Nsp13 encodes for an HLA-E-stabilizing peptide that abrogates inhibition of NKG2A-expressing NK cells. Cell Rep. 2022;38:110503. doi: 10.1016/j.celrep.2022.110503. PubMed DOI PMC

Hanna J, Goldman-Wohl D, Hamani Y, et al. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med. 2006;12:1065–1074. doi: 10.1038/nm1452. PubMed DOI

Harpur CM, Stankovic S, Kanagarajah A, et al. Enrichment of cytomegalovirus-induced NKG2C+ natural killer cells in the lung allograft. Transplantation. 2019;103:1689–1699. doi: 10.1097/TP.0000000000002545. PubMed DOI

Heatley SL, Pietra G, Lin J, et al. Polymorphism in human cytomegalovirus UL40 impacts on recognition of human leukocyte antigen-E (HLA-E) by natural killer cells. J Biol Chem. 2013;288:8679–8690. doi: 10.1074/jbc.M112.409672. PubMed DOI PMC

Hendricks DW, Balfour HH, Jr, Dunmire SK, et al. Cutting edge: NKG2C(hi)CD57+ NK cells respond specifically to acute infection with cytomegalovirus and not Epstein-Barr virus. J Immunol. 2014;192:4492–4496. doi: 10.4049/jimmunol.1303211. PubMed DOI PMC

Hikami K, Tsuchiya N, Yabe T, et al. Variations of human killer cell lectin-like receptors: common occurrence of NKG2-C deletion in the general population. Genes Immun. 2003;4:160–167. doi: 10.1038/sj.gene.6363940. PubMed DOI

Hò GT, Celik AA, Huyton T, et al. NKG2A/CD94 is a new immune receptor for HLA-G and distinguishes amino acid differences in the HLA-G heavy chain. Int J Mol Sci. 2020;21:4362. doi: 10.3390/ijms21124362. PubMed DOI PMC

Isernhagen A, Malzahn D, Viktorova E, et al. The MICA-129 dimorphism affects NKG2D signaling and outcome of hematopoietic stem cell transplantation. EMBO Mol Med. 2015;7:1480–1502. doi: 10.15252/emmm.201505246. PubMed DOI PMC

Iwaszko M, Bogunia-Kubik K. Clinical significance of the HLA-E and CD94/NKG2 interaction. Arch Immunol Ther Exp. 2011;59:353–367. doi: 10.1007/s00005-011-0137-y. PubMed DOI

Jaiswal SR, Bhakuni P, Bhagwati G, et al. Alterations in NKG2A and NKG2C subsets of natural killer cells following Epstein-Barr virus reactivation in CTLA4Ig-based haploidentical transplantation is associated with increased chronic graft-versus-host disease. Transplantation. 2020;104:e23–e30. doi: 10.1097/TP.0000000000002941. PubMed DOI

Jaiswal SR, Arunachalam J, Bhardwaj A, et al. Impact of adaptive natural killer cells, KLRC2 genotype and cytomegalovirus reactivation on late mortality in patients with severe COVID-19 lung disease. Clin Transl Immunology. 2022;11:e1359. doi: 10.1002/cti2.1359. PubMed DOI PMC

Jaiswal SR, Arunachalam J, Saifullah A, et al. Impact of an immune modulator mycobacterium-w on adaptive natural killer cells and protection against COVID-19. Front Immunol. 2022;13:887230. doi: 10.3389/fimmu.2022.887230. PubMed DOI PMC

Jasinski-Bergner S, Schmiedel D, Mandelboim O, et al. Role of HLA-G in viral infections. Front Immunol. 2022;13:826074. doi: 10.3389/fimmu.2022.826074. PubMed DOI PMC

Joyce MG, Sun PD. The structural basis of ligand recognition by natural killer cell receptors. J Biomed Biotechnol. 2011;2011:203628. doi: 10.1155/2011/203628. PubMed DOI PMC

Kaiser BK, Barahmand-Pour F, Paulsene W, et al. Interactions between NKG2x immunoreceptors and HLA-E ligands display overlapping affinities and thermodynamics. J Immunol. 2005;174:2878–2884. doi: 10.4049/jimmunol.174.5.2878. PubMed DOI

Kaiser BK, Pizarro JC, Kerns J, et al. Structural basis for NKG2A/CD94 recognition of HLA-E. Proc Natl Acad Sci USA. 2008;105:6696–6701. doi: 10.1073/pnas.0802736105. PubMed DOI PMC

Kaminski VL, Ellwanger JH, Sandrim V, et al. Influence of NKG2C gene deletion and CCR5Δ32 in pre-eclampsia-approaching the effect of innate immune gene variants in pregnancy. Int J Immunogenet. 2019;46:82–87. doi: 10.1111/iji.12416. PubMed DOI

Kordelas L, Steckel NK, Horn PA, et al. The activating NKG2C receptor is significantly reduced in NK cells after allogeneic stem cell transplantation in patients with severe graft-versus-host disease. Int J Mol Sci. 2016;17:1797. doi: 10.3390/ijms17111797. PubMed DOI PMC

Kuijpers TW, Baars PA, Dantin C, et al. Human NK cells can control CMV infection in the absence of T cells. Blood. 2008;112:914–915. doi: 10.1182/blood-2008-05-157354. PubMed DOI

Kusumi M, Yamashita T, Fujii T, et al. Expression patterns of lectin-like natural killer receptors, inhibitory CD94/NKG2A, and activating CD94/NKG2C on decidual CD56bright natural killer cells differ from those on peripheral CD56dim natural killer cells. J Reprod Immunol. 2006;70:33–42. doi: 10.1016/j.jri.2005.12.008. PubMed DOI

Lampen MH, Hassan C, Sluijter M, et al. Alternative peptide repertoire of HLA-E reveals a binding motif that is strikingly similar to HLA-A2. Mol Immunol. 2013;53:126–131. doi: 10.1016/j.molimm.2012.07.009. PubMed DOI

Lanier LL, Corliss B, Wu J, et al. Association of DAP12 with activating CD94/NKG2C NK cell receptors. Immunity. 1998;8:693–701. doi: 10.1016/s1074-7613(00)80574-9. PubMed DOI

Larsen SB, Cowley CJ, Sajjath SM, et al. Establishment, maintenance, and recall of inflammatory memory. Cell Stem Cell. 2021;28:1758–1774.e8. doi: 10.1016/j.stem.2021.07.001. PubMed DOI PMC

Lauterbach N, Wieten L, Popeijus HE, et al. HLA-E regulates NKG2C+ natural killer cell function through presentation of a restricted peptide repertoire. Hum Immunol. 2015;76:578–586. doi: 10.1016/j.humimm.2015.09.003. PubMed DOI

Li L, Tian W, Wang W, et al. NKG2C copy number variations in five distinct populations in mainland China and susceptibility to nasopharyngeal carcinoma (NPC) Hum Immunol. 2015;76:90–94. doi: 10.1016/j.humimm.2015.01.022. PubMed DOI

Llano M, Lee N, Navarro F, et al. HLA-E-bound peptides influence recognition by inhibitory and triggering CD94/NKG2 receptors: preferential response to an HLA-G-derived nonamer. Eur J Immunol. 1998;28:2854–2863. doi: 10.1002/(SICI)1521-4141(199809)28:09<2854::AID-IMMU2854>3.0.CO;2-W. PubMed DOI

López-Botet M, Muntasell A, Vilches C. The CD94/NKG2C+ NK-cell subset on the edge of innate and adaptive immunity to human cytomegalovirus infection. Semin Immunol. 2014;26:145–151. doi: 10.1016/j.smim.2014.03.002. PubMed DOI

López-Botet M, Vilches C, Redondo-Pachón D, et al. Dual role of natural killer cells on graft rejection and control of cytomegalovirus infection in renal transplantation. Front Immunol. 2017;8:166. doi: 10.3389/fimmu.2017.00166. PubMed DOI PMC

Lopez-Vergès S, Milush JM, Pandey S, et al. CD57 defines a functionally distinct population of mature NK cells in the human CD56dimCD16+ NK-cell subset. Blood. 2010;116:3865–3874. doi: 10.1182/blood-2010-04-282301. PubMed DOI PMC

Lopez-Vergès S, Milush JM, Schwartz BS, et al. Expansion of a unique CD57+NKG2Chi natural killer cell subset during acute human cytomegalovirus infection. Proc Natl Acad Sci USA. 2011;108:14725–14732. doi: 10.1073/pnas.1110900108. PubMed DOI PMC

Malone D, Lunemann S, Hengst J, et al. Cytomegalovirus-driven adaptive-like natural killer cell expansions are unaffected by concurrent chronic hepatitis virus infections. Front Immunol. 2017;8:525. doi: 10.3389/fimmu.2017.00525. PubMed DOI PMC

Marín R, Ruiz-Cabello F, Pedrinaci S, et al. Analysis of HLA-E expression in human tumors. Immunogenetics. 2003;54:767–775. doi: 10.1007/s00251-002-0526-9. PubMed DOI

Martínez-Rodríguez JE, Munné-Collado J, Rasal R, et al. Expansion of the NKG2C+ natural killer-cell subset is associated with high-risk carotid atherosclerotic plaques in seropositive patients for human cytomegalovirus. Arterioscler Thromb Vasc Biol. 2013;33:2653–2659. doi: 10.1161/ATVBAHA.113.302163. PubMed DOI

Maucourant C, Filipovic I, Ponzetta A, et al. Natural killer cell immunotypes related to COVID-19 disease severity. Sci Immunol. 2020;5:eabd832. doi: 10.1126/sciimmunol.abd6832. PubMed DOI PMC

Mehta RS, Shpall EJ, Rezvani K. Cord blood as a source of natural killer cells. Front Med. 2016;2:93. doi: 10.3389/fmed.2015.00093. PubMed DOI PMC

Meresse B, Curran SA, Ciszewski C, et al. Reprogramming of CTLs into natural killer-like cells in celiac disease. J Exp Med. 2006;203:1343–1355. doi: 10.1084/jem.20060028. PubMed DOI PMC

Merino A, Zhang B, Dougherty P, et al. Chronic stimulation drives human NK cell dysfunction and epigenetic reprograming. J Clin Invest. 2019;129:3770–3785. doi: 10.1172/JCI125916. PubMed DOI PMC

Michaëlsson J, Teixeira de Matos C, Achour A, et al. A signal peptide derived from hsp60 binds HLA-E and interferes with CD94/NKG2A recognition. J Exp Med. 2002;196:1403–1414. doi: 10.1084/jem.20020797. PubMed DOI PMC

Miyashita R, Tsuchiya N, Hikami K, et al. Molecular genetic analyses of human NKG2C (KLRC2) gene deletion. Int Immunol. 2004;16:163–168. doi: 10.1093/intimm/dxh013. PubMed DOI

Monsiváis-Urenda A, Noyola-Cherpitel D, Hernández-Salinas A, et al. Influence of human cytomegalovirus infection on the NK cell receptor repertoire in children. Eur J Immunol. 2010;40:1418–1427. doi: 10.1002/eji.200939898. PubMed DOI

Moraru M, Cisneros E, Gómez-Lozano N, et al. Host genetic factors in susceptibility to herpes simplex type 1 virus infection: contribution of polymorphic genes at the interface of innate and adaptive immunity. J Immunol. 2012;188:4412–4420. doi: 10.4049/jimmunol.1103434. PubMed DOI

Muñoz-Cobo B, Giménez E, Solano C, et al. An evaluation of the role of NKG2C+ natural killer cells in protection from cytomegalovirus DNAemia early following allogeneic stem cell transplantation. J Med Virol. 2014;86:806–811. doi: 10.1002/jmv.23742. PubMed DOI

Muntasell A, López-Montañés M, Vera A, et al. NKG2C zygosity influences CD94/NKG2C receptor function and the NK-cell compartment redistribution in response to human cytomegalovirus. Eur J Immunol. 2013;43:3268–3278. doi: 10.1002/eji.201343773. PubMed DOI

Muntasell A, Pupuleku A, Cisneros E, et al. Relationship of nkg2c copy number with the distribution of distinct cytomegalovirus-induced adaptive NK cell subsets. J Immunol. 2016;196:3818–3827. doi: 10.4049/jimmunol.1502438. PubMed DOI

Murad S, Michen S, Becker A, et al. NKG2C+ NK cells for immunotherapy of glioblastoma multiforme. Int J Mol Sci. 2022;23:5857. doi: 10.3390/ijms23105857. PubMed DOI PMC

Muta T, Yoshihiro T, Jinnouchi F, et al. Expansion of NKG2C-expressing natural killer cells after umbilical cord blood transplantation in a patient with peripheral T-cell lymphoma with cytotoxic molecules. Intern Med. 2018;57:861–866. doi: 10.2169/internalmedicine.9437-17. PubMed DOI PMC

Navarro F, Llano M, Bellón T, et al. The ILT2(LIR1) and CD94/NKG2A NK cell receptors respectively recognize HLA-G1 and HLA-E molecules co-expressed on target cells. Eur J Immunol. 1999;29:277–283. doi: 10.1002/(SICI)1521-4141(199901)29:01<277::AID-IMMU277>3.0.CO;2-4. PubMed DOI

Noyola DE, Fortuny C, Muntasell A, et al. Influence of congenital human cytomegalovirus infection and the NKG2C genotype on NK-cell subset distribution in children. Eur J Immunol. 2012;42:3256–3266. doi: 10.1002/eji.201242752. PubMed DOI

Noyola DE, Alarcón A, Noguera-Julian A, et al. Dynamics of the NK-cell subset redistribution induced by cytomegalovirus infection in preterm infants. Hum Immunol. 2015;76:118–123. doi: 10.1016/j.humimm.2015.01.017. PubMed DOI

Oliviero B, Varchetta S, Paudice E, et al. Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections. Gastroenterology. 2009;137:1151–1160.e11607. doi: 10.1053/j.gastro.2009.05.047. PubMed DOI

Onno M, Pangault C, Le Friec G, et al. Modulation of HLA-G antigens expression by human cytomegalovirus: specific induction in activated macrophages harboring human cytomegalovirus infection. J Immunol. 2000;164:6426–6434. doi: 10.4049/jimmunol.164.12.6426. PubMed DOI

Park KS, Park JH, Song YW. Inhibitory NKG2A and activating NKG2D and NKG2C natural killer cell receptor genes: susceptibility for rheumatoid arthritis. Tissue Antigens. 2008;72:342–346. doi: 10.1111/j.1399-0039.2008.01110.x. PubMed DOI

Pascual-Guardia S, Ataya M, Ramírez-Martínez I, et al. Adaptive NKG2C+ natural killer cells are related to exacerbations and nutritional abnormalities in COPD patients. Respir Res. 2020;21:63. doi: 10.1186/s12931-020-1323-4. PubMed DOI PMC

Patel F, Marusina AI, Duong C, et al. NKG2C, HLA-E and their association with psoriasis. Exp Dermatol. 2013;22:797–799. doi: 10.1111/exd.12280. PubMed DOI PMC

Paul S, Shilpi LG. Role of gamma-delta (γδ) T cells in autoimmunity. J Leukoc Biol. 2015;97:259–271. doi: 10.1189/jlb.3RU0914-443R. PubMed DOI

Pende D, Falco M, Vitale M, et al. Killer Ig-like receptors (KIRs): their role in NK cell modulation and developments leading to their clinical exploitation. Front Immunol. 2019;10:1179. doi: 10.3389/fimmu.2019.01179. PubMed DOI PMC

Petitdemange C, Becquart P, Wauquier N, et al. Unconventional repertoire profile is imprinted during acute chikungunya infection for natural killer cells polarization toward cytotoxicity. PLoS Pathog. 2011;7:e1002268. doi: 10.1371/journal.ppat.1002268. PubMed DOI PMC

Petitdemange C, Wauquier N, Devilliers H, et al. Longitudinal analysis of natural killer cells in dengue virus-infected patients in comparison to chikungunya and chikungunya/dengue virus-infected patients. PLoS Negl Tropical Dis. 2016;10:e0004499. doi: 10.1371/journal.pntd.0004499. PubMed DOI PMC

Picardi A, Mengarelli A, Marino M, et al. Up-regulation of activating and inhibitory NKG2 receptors in allogeneic and autologous hematopoietic stem cell grafts. J Exp Clin Cancer Res. 2015;34:98. doi: 10.1186/s13046-015-0213-y. PubMed DOI PMC

Prašnikar E, Perdih A, Borišek J. Nonameric peptide orchestrates signal transduction in the activating HLA-E/NKG2C/CD94 immune complex as revealed by all-atom simulations. Int J Mol Sci. 2021;22:6670. doi: 10.3390/ijms22136670. PubMed DOI PMC

Prod'homme V, Tomasec P, Cunningham C, et al. Human cytomegalovirus UL40 signal peptide regulates cell surface expression of the NK cell ligands HLA-E and gpUL18. J Immunol. 2012;188:2794–2804. doi: 10.4049/jimmunol.1102068. PubMed DOI PMC

Quatrini L, Della Chiesa M, Sivori S, et al. Human NK cells, their receptors and function. Eur J Immunol. 2021;51:1566–1579. doi: 10.1002/eji.202049028. PubMed DOI PMC

Rangel-Ramírez VV, Garcia-Sepulveda CA, Escalante-Padrón F, et al. NKG2C gene deletion in the Mexican population and lack of association to respiratory viral infections. Int J Immunogenet. 2014;41:126–130. doi: 10.1111/iji.12104. PubMed DOI

Redondo-Pachón D, Crespo M, Yélamos J, et al. Adaptive NKG2C+ NK cell response and the risk of cytomegalovirus infection in kidney transplant recipients. J Immunol. 2017;198:94–101. doi: 10.4049/jimmunol.1601236. PubMed DOI

Riese P, Trittel S, Pathirana RD, et al. Responsiveness to influenza vaccination correlates with NKG2C-expression on NK cells. Vaccines. 2020;8:281. doi: 10.3390/vaccines8020281. PubMed DOI PMC

Rölle A, Pollmann J, Ewen EM, et al. IL-12-producing monocytes and HLA-E control HCMV-driven NKG2C+ NK cell expansion. J Clin Invest. 2014;124:5305–5316. doi: 10.1172/JCI77440. PubMed DOI PMC

Rückert T, Lareau CA, Mashreghi MF, et al. Clonal expansion and epigenetic inheritance of long-lasting NK cell memory. Nat Immunol. 2022;23:1551–1563. doi: 10.1038/s41590-022-01327-7. PubMed DOI PMC

Sáez-Borderías A, Romo N, Magri G, et al. IL-12-dependent inducible expression of the CD94/NKG2A inhibitory receptor regulates CD94/NKG2C+ NK cell function. J Immunol. 2009;182:829–836. doi: 10.4049/jimmunol.182.2.829. PubMed DOI

Saghafian-Hedengren S, Sohlberg E, Theorell J, et al. Epstein-Barr virus coinfection in children boosts cytomegalovirus-induced differentiation of natural killer cells. J Virol. 2013;87:13446–13455. doi: 10.1128/JVI.02382-13. PubMed DOI PMC

Schlums H, Cichocki F, Tesi B, et al. Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function. Immunity. 2015;42:443–456. doi: 10.1016/j.immuni.2015.02.008. PubMed DOI PMC

Seo J, Park JS, Nam JH, et al. Association of CD94/NKG2A, CD94/NKG2C, and its ligand HLA-E polymorphisms with Behcet's disease. Tissue Antigens. 2007;70:307–313. doi: 10.1111/j.1399-0039.2007.00907.x. PubMed DOI

Shemesh A, Su Y, Calabrese DR, et al. Diminished cell proliferation promotes natural killer cell adaptive-like phenotype by limiting FcεRIγ expression. J Exp Med. 2022;219:e20220551. doi: 10.1084/jem.20220551. PubMed DOI PMC

Shum BP, Flodin LR, Muir DG, et al. Conservation and variation in human and common chimpanzee CD94 and NKG2 genes. J Immunol. 2002;168:240–252. doi: 10.4049/jimmunol.168.1.240. PubMed DOI

Siemaszko J, Marzec-Przyszlak A, Bogunia-Kubik K. NKG2D natural killer cell receptor-a short description and potential clinical applications. Cells. 2021;10:1420. doi: 10.3390/cells10061420. PubMed DOI PMC

Siewiera J, El Costa H, Tabiasco J, et al. Human cytomegalovirus infection elicits new decidual natural killer cell effector functions. PLoS Pathog. 2013;9:e1003257. doi: 10.1371/journal.ppat.1003257. PubMed DOI PMC

Tarantino N, Leboyer M, Bouleau A, et al. Natural killer cells in first-episode psychosis: an innate immune signature? Mol Psychiatry. 2021;26:5297–5306. doi: 10.1038/s41380-020-01008-7. PubMed DOI

Thomas R, Low HZ, Kniesch K, et al. NKG2C deletion is a risk factor of HIV infection. AIDS Res Hum Retroviruses. 2012;28:844–851. doi: 10.1089/AID.2011.0253. PubMed DOI PMC

Tomasec P, Braud VM, Rickards C, et al. Surface expression of HLA-E, an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40. Science. 2000;287:1031. doi: 10.1126/science.287.5455.1031. PubMed DOI

Toson B, Michita RT, Matte M, et al. Assessment of NKG2C copy number variation in HIV-1 infection susceptibility, and considerations about the potential role of lacking receptors and virus infection. J Hum Genet. 2022;67:475–479. doi: 10.1038/s10038-022-01029-w. PubMed DOI PMC

Tsamadou C, Fürst D, Vucinic V, et al. Human leukocyte antigen-E mismatch is associated with better hematopoietic stem cell transplantation outcome in acute leukemia patients. Haematologica. 2017;102:1947–1955. doi: 10.3324/haematol.2017.169805. PubMed DOI PMC

Tsamadou C, Fürst D, Wang T, et al. Donor HLA-E status associates with disease-free survival and transplant-related mortality after non in vivo T cell-depleted HSCT for acute leukemia. Biol Blood Marrow Transplant. 2019;25:2357–2365. doi: 10.1016/j.bbmt.2019.08.007. PubMed DOI PMC

Ulbrecht M, Martinozzi S, Grzeschik M, et al. Cutting edge: the human cytomegalovirus UL40 gene product contains a ligand for HLA-E and prevents NK cell-mediated lysis. J Immunol. 2000;164:5019–5022. doi: 10.4049/jimmunol.164.10.5019. PubMed DOI

Valés-Gómez M, Reyburn HT, Erskine RA, et al. Kinetics and peptide dependency of the binding of the inhibitory NK receptor CD94/NKG2-A and the activating receptor CD94/NKG2-C to HLA-E. EMBO J. 1999;18:4250–4260. doi: 10.1093/emboj/18.15.4250. PubMed DOI PMC

Vietzen H, Pollak K, Honsig C, et al. NKG2C deletion is a risk factor for human cytomegalovirus viremia and disease after lung transplantation. J Infect Dis. 2018;217:802–806. doi: 10.1093/infdis/jix608. PubMed DOI

Vietzen H, Zoufaly A, Traugott M, et al. Deletion of the NKG2C receptor encoding KLRC2 gene and HLA-E variants are risk factors for severe COVID-19. Genet Med. 2021;23:963–967. doi: 10.1038/s41436-020-01077-7. PubMed DOI PMC

Vietzen H, Hartenberger S, Aberle SW, et al. Dissection of the NKG2C NK cell response against Puumala orthohantavirus. PLoS Negl Trop Dis. 2021;15:e0010006. doi: 10.1371/journal.pntd.0010006. PubMed DOI PMC

Vilchez JR, Torres-Moreno D, Martínez-Senac MM, et al. Evaluation of the association of NKG2C copy number variations with susceptibility to human papillomavirus-induced cervical lesions. Hum Immunol. 2013;74:1352–1356. doi: 10.1016/j.humimm.2013.07.006. PubMed DOI

Vivier E, Raulet DH, Moretta A, et al. Innate or adaptive immunity? The example of natural killer cells. Science. 2011;331:44–49. doi: 10.1126/science.1198687. PubMed DOI PMC

Vivier E, Artis D, Colonna M, et al. Innate lymphoid cells: 10 years on. Cell. 2018;174:1054–1066. doi: 10.1016/j.cell.2018.07.017. PubMed DOI

Wada H, Matsumoto N, Maenaka K, et al. The inhibitory NK cell receptor CD94/NKG2A and the activating receptor CD94/NKG2C bind the top of HLA-E through mostly shared but partly distinct sets of HLA-E residues. Eur J Immunol. 2004;34:81–90. doi: 10.1002/eji.200324432. PubMed DOI

Waters S, Lee S, Affandi JS, et al. The effect of genetic variants affecting NK cell function on cardiovascular health and the burden of CMV. Hum Immunol. 2017;78:747–751. doi: 10.1016/j.humimm.2017.10.003. PubMed DOI

Yan WH, Lin A, Chen BG, et al. Induction of both membrane-bound and soluble HLA-G expression in active human cytomegalovirus infection. J Infect Dis. 2009;200:820–826. doi: 10.1086/604733. PubMed DOI

Yan W, Wu D, Wang X, et al. Upregulation of NKG2C+ natural killer cells, TLR-2 expression on monocytes and downregulation of regulatory T-cells influence PEG-IFN treatment efficacy in entecavir-suppressed patients with CHB. Antiviral Ther. 2015;20:591–602. doi: 10.3851/IMP2953. PubMed DOI

Yang C, Siebert JR, Burns R, et al. Heterogeneity of human bone marrow and blood natural killer cells defined by single-cell transcriptome. Nat Commun. 2019;10:3931. doi: 10.1038/s41467-019-11947-7. PubMed DOI PMC

Yu XX, Shang QN, Liu XF, et al. Donor NKG2C homozygosity contributes to CMV clearance after haploidentical transplantation. JCI Insight. 2022;7:e149120. doi: 10.1172/jci.insight.149120. PubMed DOI PMC

Zaguia F, Saikali P, Ludwin S, et al. Cytotoxic NKG2C+ CD4 T cells target oligodendrocytes in multiple sclerosis. J Immunol. 2013;190:2510–2518. doi: 10.4049/jimmunol.1202725. PubMed DOI

Zeddou M, Rahmouni S, Vandamme A, et al. Downregulation of CD94/NKG2A inhibitory receptors on CD8+ T cells in HIV infection is more pronounced in subjects with detected viral load than in their aviraemic counterparts. Retrovirology. 2007;4:72. doi: 10.1186/1742-4690-4-72. PubMed DOI PMC

Zeng X, Chen H, Gupta R, et al. Deletion of the activating NKG2C receptor and a functional polymorphism in its ligand HLA-E in psoriasis susceptibility. Exp Dermatol. 2013;22:679–681. doi: 10.1111/exd.12233. PubMed DOI PMC

Zhou J, Amran FS, Kramski M, et al. An NK cell population lacking FcRγ is expanded in chronically infected HIV patients. J Immunol. 2015;194:4688–4697. doi: 10.4049/jimmunol.1402448. PubMed DOI

Zuo W, Zhao X. Natural killer cells play an important role in virus infection control: antiviral mechanism, subset expansion and clinical application. Clin Immunol. 2021;227:108727. doi: 10.1016/j.clim.2021.108727. PubMed DOI PMC

Find record

Citation metrics

Loading data ...

Archiving options

Loading data ...