Skip to main content

Advertisement

Log in

Expression of NKp30, NKp46 and DNAM-1 activating receptors on resting and IL-2 activated NK cells from healthy donors according to CMV-serostatus and age

  • Research Article
  • Published:
Biogerontology Aims and scope Submit manuscript

Abstract

Human natural killer (NK) cells are innate lymphoid cells with capacity to kill tumor cells and virus-infected cells. According to the expression of CD56 and CD16 several NK cell subsets have been identified, a major CD56dimCD16+ subpopulation characterized by higher cytotoxic capacity, two CD56bright subsets (CD16−and CD16+) that represent different maturation stages and the fourth CD56−CD16+ subset that correspond to activated dysfunctional NK cells. Previous studies have shown quantitative changes in the frequency, phenotype and distribution of NK cell subsets depending on CMV-serostatus and age. We have analyzed the expression of NKp30, NKp46 and DNAM-1 NK activating receptors on resting and IL-2 activated NK cells from CMV-seronegative and seropositive healthy young donors and from CMV-seropositive elderly individuals. Our results showed that CMV-serostatus of healthy young donors is associated with phenotypic differences on both CD56bright and CD56dim NK cells with an increase of NKp46 and a decrease of NKp30 expression respectively. A reduced expression of DNAM-1 related to ageing and a lower NKp30 expression associated with CMV-seropositivity were observed. The expression of NKp46 and NKp30 was lower in CD57+ NK cells while the expression of DNAM-1 was increased. In vitro NK cell activation by IL-2 increased the expression of NKp46 and NKp30. In summary, both age and CMV-serostatus influence the expression of these cytotoxicity activating receptors that will have functional consequences. In elderly donors is difficult to isolate age from the effect of chronic CMV infection since in our study all elderly donors were CMV-seropositive. The possibility of modulating the expression of these activating receptors by cytokines such as IL-2 may open new opportunities for improving age-associated deterioration of NK cell function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Arnon TI, Achdout H, Levi O, Markel G, Saleh N, Katz G, Gazit R, Gonen-Gross T, Hanna J, Nahari E, Porgador A, Honigman A, Plachter B, Mevorach D, Wolf DG, Mandelboim O (2005) Inhibition of the NKp30 activating receptor by pp65 of human cytomegalovirus. Nat Immunol 6:515–523

    Article  CAS  PubMed  Google Scholar 

  • Beli E, Duriancik DM, Clinthorne JF, Lee T, Kim S, Gardner EM (2014) Natural killer cell development and maturation in aged mice. Mech Ageing Dev 135:33–40

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Beziat V, Duffy D, Quoc SN, Le Garff-Tavernier M, Decocq J, Combadiere B, Debre P, Vieillard V (2011) CD56brightCD16+ NK cells: a functional intermediate stage of NK cell differentiation. J Immunol 186:6753–6761

    Article  CAS  PubMed  Google Scholar 

  • Beziat V, Dalgard O, Asselah T, Halfon P, Bedossa P, Boudifa A, Hervier B, Theodorou I, Martinot M, Debre P, Bjorkstrom NK, Malmberg KJ, Marcellin P, Vieillard V (2012) CMV drives clonal expansion of NKG2C(+) NK cells expressing self-specific KIRs in chronic hepatitis patients. Eur J Immunol 42:447–457

    Article  CAS  PubMed  Google Scholar 

  • Biassoni R, Cantoni C, Pende D, Sivori S, Parolini S, Vitale M, Bottino C, Moretta A (2001) Human natural killer cell receptors and co-receptors. Immunol Rev 181:203–214

    Article  CAS  PubMed  Google Scholar 

  • Bjorkstrom NK, Ljunggren HG, Sandberg JK (2010a) CD56 negative NK cells: origin, function, and role in chronic viral disease. Trends Immunol 31:401–406

    Article  PubMed  Google Scholar 

  • Bjorkstrom NK, Riese P, Heuts F, Andersson S, Fauriat C, Ivarsson MA, Bjorklund AT, Flodstrom-Tullberg M, Michaelsson J, Rottenberg ME, Guzman CA, Ljunggren HG, Malmberg KJ (2010b) Expression patterns of NKG2A, KIR, and CD57 define a process of CD56dim NK cell differentiation uncoupled from NK cell education. Blood 116:3853–3864

    Article  PubMed  Google Scholar 

  • Bjorkstrom NK, Lindgren T, Stoltz M, Fauriat C, Braun M, Evander M, Michaelsson J, Malmberg KJ, Klingstrom J, Ahlm C, Ljunggren HG (2011) Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus. J Exp Med 208:13–21

    Article  PubMed Central  PubMed  Google Scholar 

  • Borrego F, Alonso MC, Galiani MD, Carracedo J, Ramirez R, Ostos B, Pena J, Solana R (1999) NK phenotypic markers and IL2 response in NK cells from elderly people. Exp Gerontol 34:253–265

    Article  CAS  PubMed  Google Scholar 

  • Brehm C, Huenecke S, Quaiser A, Esser R, Bremm M, Kloess S, Soerensen J, Kreyenberg H, Seidl C, Becker PS, Muhl H, Klingebiel T, Bader P, Passweg JR, Schwabe D, Koehl U (2011) IL-2 stimulated but not unstimulated NK cells induce selective disappearance of peripheral blood cells: concomitant results to a phase I/II study. PLoS One 6:e27351

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Camous X, Pera A, Solana R, Larbi A (2012) NK cells in healthy aging and age-associated diseases. J Biomed Biotechnol 2012:195956

    Article  PubMed Central  PubMed  Google Scholar 

  • Campos C, Pera A, Lopez-Fernandez I, Alonso C, Tarazona R, Solana R (2014a) Proinflammatory status influences NK cells subsets in the elderly. Immunol Lett 162:298–302

    Article  CAS  PubMed  Google Scholar 

  • Campos C, Pera A, Sanchez-Correa B, Alonso C, Lopez-Fernandez I, Morgado S, Tarazona R, Solana R (2014b) Effect of age and CMV on NK cell subpopulations. Exp Gerontol 54:130–137

    Article  CAS  PubMed  Google Scholar 

  • Cannon MJ, Schmid DS, Hyde TB (2010) Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol 20:202–213

    Article  PubMed  Google Scholar 

  • Chidrawar SM, Khan N, Chan YL, Nayak L, Moss PA (2006) Ageing is associated with a decline in peripheral blood CD56bright NK cells. Immun Ageing 3:10

    Article  PubMed Central  PubMed  Google Scholar 

  • Chiu BC, Martin BE, Stolberg VR, Chensue SW (2013) The host environment is responsible for aging-related functional NK cell deficiency. J. Immunol. 191:4688–4698

    Article  CAS  PubMed  Google Scholar 

  • Cichocki F, Miller JS, Anderson SK, Bryceson YT (2013) Epigenetic regulation of NK cell differentiation and effector functions. Front Immunol 4:55

    Article  PubMed Central  PubMed  Google Scholar 

  • Cooper MA, Fehniger TA, Caligiuri MA (2001) The biology of human natural killer-cell subsets. Trends Immunol 22:633–640

    Article  CAS  PubMed  Google Scholar 

  • DelaRosa O, Pawelec G, Peralbo E, Wikby A, Mariani E, Mocchegiani E, Tarazona R, Solana R (2006) Immunological biomarkers of ageing in man: changes in both innate and adaptive immunity are associated with health and longevity. Biogerontology 7:471–481

    Article  CAS  PubMed  Google Scholar 

  • Della CM, Falco M, Podesta M, Locatelli F, Moretta L, Frassoni F, Moretta A (2012) Phenotypic and functional heterogeneity of human NK cells developing after umbilical cord blood transplantation: a role for human cytomegalovirus? Blood 119:399–410

    Article  Google Scholar 

  • deOry F, Ramirez R, Garcia CL, Leon P, Sagues MJ, Sanz JC (2004) Is there a change in cytomegalovirus seroepidemiology in Spain? Eur J Epidemiol 19:85–89

    Article  CAS  Google Scholar 

  • deOry-Manchon F, Sanz-Moreno JC, Castaneda-Lopez R, Ramirez-Fernandez R, Leon-Rega P, Pachon del Amo I (2001) Cytomegalovirus seroepidemiology in the community of Madrid. Rev Esp Salud Publica 75:55–62

    CAS  Google Scholar 

  • deRham C, Ferrari-Lacraz S, Jendly S, Schneiter G, Dayer JM, Villard J (2007) The proinflammatory cytokines IL-2, IL-15 and IL-21 modulate the repertoire of mature human natural killer cell receptors. Arthritis Res Ther 9:R125

    Article  Google Scholar 

  • Derhovanessian E, Larbi A, Pawelec G (2009) Biomarkers of human immunosenescence: impact of Cytomegalovirus infection. Curr Opin Immunol 21:440–445

    Article  CAS  PubMed  Google Scholar 

  • Gayoso I, Sanchez-Correa B, Campos C, Alonso C, Pera A, Casado JG, Morgado S, Tarazona R, Solana R (2011) Immunosenescence of human natural killer cells. J Innate Immun 3:337–343

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez VD, Falconer K, Bjorkstrom NK, Blom KG, Weiland O, Ljunggren HG, Alaeus A, Sandberg JK (2009) Expansion of functionally skewed CD56-negative NK cells in chronic hepatitis C virus infection: correlation with outcome of pegylated IFN-alpha and ribavirin treatment. J Immunol 183:6612–6618

    Article  CAS  PubMed  Google Scholar 

  • Gratacap-Cavallier B, Bosson JL, Morand P, Dutertre N, Chanzy B, Jouk PS, Vandekerckhove C, Cart-Lamy P, Seigneurin JM (1998) Cytomegalovirus seroprevalence in french pregnant women: parity and place of birth as major predictive factors. Eur J Epidemiol 14:147–152

    Article  CAS  PubMed  Google Scholar 

  • Grubeck-Loebenstein B, Della BS, Iorio AM, Michel JP, Pawelec G, Solana R (2009) Immunosenescence and vaccine failure in the elderly. Aging Clin Exp Res 21:201–209

    Article  CAS  PubMed  Google Scholar 

  • Guma M, Angulo A, Vilches C, Gomez-Lozano N, Malats N, Lopez-Botet M (2004) Imprint of human cytomegalovirus infection on the NK cell receptor repertoire. Blood 104:3664–3671

    Article  CAS  PubMed  Google Scholar 

  • Guma M, Cabrera C, Erkizia I, Bofill M, Clotet B, Ruiz L, Lopez-Botet M (2006) 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 194:38–41

    Article  PubMed  Google Scholar 

  • Hamerman JA, Ogasawara K, Lanier LL (2005) NK cells in innate immunity. Curr Opin Immunol 17:29–35

    Article  CAS  PubMed  Google Scholar 

  • Koch S, Solana R, DelaRosa O, Pawelec G (2006) Human cytomegalovirus infection and T cell immunosenescence: a mini review. Mech Ageing Dev 127:538–543

    Article  CAS  PubMed  Google Scholar 

  • Koch S, Larbi A, Ozcelik D, Solana R, Gouttefangeas C, Attig S, Wikby A, Strindhall J, Franceschi C, Pawelec G (2007) Cytomegalovirus infection: a driving force in human T cell immunosenescence. Ann N Y Acad Sci 1114:23–35

    Article  CAS  PubMed  Google Scholar 

  • Lanier LL (2008) Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol 9:495–502

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Larbi A, Franceschi C, Mazzatti D, Solana R, Wikby A, Pawelec G (2008) Aging of the immune system as a prognostic factor for human longevity. Physiology. (Bethesda.) 23:64–74

    Article  CAS  Google Scholar 

  • Lopez-Verges S, Milush JM, Pandey S, York VA, Arakawa-Hoyt J, Pircher H, Norris PJ, Nixon DF, Lanier LL (2010) CD57 defines a functionally distinct population of mature NK cells in the human CD56dimCD16+ NK cell subset. Blood 116:3865–3874

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lopez-Verges S, Milush JM, Schwartz BS, Pando MJ, Jarjoura J, York VA, Houchins JP, Miller S, Kang SM, Norris PJ, Nixon DF, Lanier LL (2011) Expansion of a unique CD57NKG2Chi natural killer cell subset during acute human cytomegalovirus infection. Proc Natl Acad Sci U. S. A 108:14725–14732

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Magri G, Muntasell A, Romo N, Saez-Borderias A, Pende D, Geraghty DE, Hengel H, Angulo A, Moretta A, Lopez-Botet M (2011) NKp46 and DNAM-1 NK-cell receptors drive the response to human cytomegalovirus-infected myeloid dendritic cells overcoming viral immune evasion strategies. Blood 117:848–856

    Article  CAS  PubMed  Google Scholar 

  • Marcus A, Raulet DH (2013) Evidence for natural killer cell memory. Curr Biol 23:R817–R820

    Article  CAS  PubMed  Google Scholar 

  • Mariani E, Sgobbi S, Meneghetti A, Tadolini M, Tarozzi A, Sinoppi M, Cattini L, Facchini A (1996) Perforins in human cytolytic cells: the effect of age. Mech Ageing Dev 92:195–209

    Article  CAS  PubMed  Google Scholar 

  • Mariani E, Mariani AR, Meneghetti A, Tarozzi A, Cocco L, Facchini A (1998) Age-dependent decreases of NK cell phosphoinositide turnover during spontaneous but not Fc-mediated cytolytic activity. Int Immunol 10:981–989

    Article  CAS  PubMed  Google Scholar 

  • Mavilio D, Lombardo G, Benjamin J, Kim D, Follman D, Marcenaro E, O’Shea MA, Kinter A, Kovacs C, Moretta A, Fauci AS (2005) Characterization of CD56-/CD16+ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals. Proc Natl Acad Sci USA 102:2886–2891

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Milush JM, Lopez-Verges S, York VA, Deeks SG, Martin JN, Hecht FM, Lanier LL, Nixon DF (2013) CD56negCD16+ NK cells are activated mature NK cells with impaired effector function during HIV-1 infection. Retrovirology 10:158

    Article  PubMed Central  PubMed  Google Scholar 

  • Min-Oo G, Kamimura Y, Hendricks DW, Nabekura T, Lanier LL (2013) Natural killer cells: walking three paths down memory lane. Trends Immunol 34:251–258

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Monsivais-Urenda A, Noyola-Cherpitel D, Hernandez-Salinas A, Garcia-Sepulveda C, Romo N, Baranda L, Lopez-Botet M, Gonzalez-Amaro R (2010) Influence of human cytomegalovirus infection on the NK cell receptor repertoire in children. Eur J Immunol 40:1418–1427

    Article  CAS  PubMed  Google Scholar 

  • Moretta A, Bottino C, Vitale M, Pende D, Cantoni C, Mingari MC, Biassoni R, Moretta L (2001) Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol 19:197–223

    Article  CAS  PubMed  Google Scholar 

  • Moretta A, Marcenaro E, Parolini S, Ferlazzo G, Moretta L (2008) NK cells at the interface between innate and adaptive immunity. Cell Death Differ 15:226–233

    Article  CAS  PubMed  Google Scholar 

  • Muntasell A, Costa-Garcia M, Vera A, Marina-Garcia N, Kirschning CJ, Lopez-Botet M (2013a) Priming of NK cell anti-viral effector mechanisms by direct recognition of human cytomegalovirus. Front Immunol 4:40

    Article  PubMed Central  PubMed  Google Scholar 

  • Muntasell A, Vilches C, Angulo A, Lopez-Botet M (2013b) Adaptive reconfiguration of the human NK-cell compartment in response to cytomegalovirus: a different perspective of the host-pathogen interaction. Eur J Immunol 43:1133–1141

    Article  CAS  PubMed  Google Scholar 

  • Nabekura T, Kanaya M, Shibuya A, Fu G, Gascoigne NR, Lanier LL (2014) Costimulatory molecule DNAM-1 is essential for optimal differentiation of memory natural killer cells during mouse cytomegalovirus infection. Immunity 40:225–234

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nielsen CM, White MJ, Goodier MR, Riley EM (2013) Functional significance of cd57 expression on human nk cells and relevance to disease. Front Immunol 4:422

    Article  PubMed Central  PubMed  Google Scholar 

  • Pawelec G, Derhovanessian E (2011) Role of CMV in immune senescence. Virus Res 157:175–179

    Article  CAS  PubMed  Google Scholar 

  • Pawelec G, Akbar A, Caruso C, Solana R, Grubeck-Loebenstein B, Wikby A (2005) Human immunosenescence: is it infectious? Immunol Rev 205:257–268

    Article  CAS  PubMed  Google Scholar 

  • Pawelec G, McElhaney JE, Aiello AE, Derhovanessian E (2012) The impact of CMV infection on survival in older humans. Curr Opin Immunol 24:507–511

    Article  CAS  PubMed  Google Scholar 

  • Petitdemange C, Becquart P, Wauquier N, Beziat V, Debre P, Leroy EM, Vieillard V (2011) Unconventional repertoire profile is imprinted during acute chikungunya infection for natural killer cells polarization toward cytotoxicity. PLoS Pathog 7:e1002268

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Poli A, Michel T, Theresine M, Andres E, Hentges F, Zimmer J (2009) CD56bright natural killer (NK) cells: an important NK cell subset. Immunology 126:458–465

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Prod’homme V, Sugrue DM, Stanton RJ, Nomoto A, Davies J, Rickards CR, Cochrane D, Moore M, Wilkinson GW, Tomasec P (2010) Human cytomegalovirus UL141 promotes efficient downregulation of the natural killer cell activating ligand CD112. J Gen Virol 91:2034–2039

    Article  PubMed Central  PubMed  Google Scholar 

  • Rajagopalan S, Long EO (2005) Viral evasion of NK-cell activation. Trends Immunol 26:403–405

    Article  CAS  PubMed  Google Scholar 

  • Romo N, Magri G, Muntasell A, Heredia G, Baia D, Angulo A, Guma M, Lopez-Botet M (2011) Natural killer cell-mediated response to human cytomegalovirus-infected macrophages is modulated by their functional polarization. J Leukoc Biol 90:717–726

    Article  CAS  PubMed  Google Scholar 

  • Sanchez-Correa B, Gayoso I, Bergua JM, Casado JG, Morgado S, Solana R, Tarazona R (2012) Decreased expression of DNAM-1 on NK cells from acute myeloid leukemia patients. Immunol Cell Biol 90:109–115

    Article  CAS  PubMed  Google Scholar 

  • Solana R, Mariani E (2000) NK and NK/T cells in human senescence. Vaccine 18:1613–1620

    Article  CAS  PubMed  Google Scholar 

  • Solana R, Pawelec G, Tarazona R (2006) Aging and innate immunity. Immunity 24:491–494

    Article  CAS  PubMed  Google Scholar 

  • Solana R, Tarazona R, Gayoso I, Lesur O, Dupuis G, Fulop T (2012) Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans. Semin Immunol 24:331–341

    Article  CAS  PubMed  Google Scholar 

  • Solana R, Campos C, Pera A, Tarazona R (2014) Shaping of NK cell subsets by aging. Curr Opin Immunol 29C:56–61

    Article  Google Scholar 

  • Tarazona R, Casado JG, DelaRosa O, Torre-Cisneros J, Villanueva JL, Sanchez B, Galiani MD, Gonzalez R, Solana R, Pena J (2002) Selective depletion of CD56(dim) NK cell subsets and maintenance of CD56(bright) NK cells in treatment-naive HIV-1-seropositive individuals. J Clin Immunol 22:176–183

    Article  CAS  PubMed  Google Scholar 

  • Tarazona R, Gayoso I, Alonso C, Pita-Lopez ML, Peralbo E, Casado JG, Sanchez-Correa B, Morgado S, Solana R (2009) NK Cells in Human Ageing. In: Fulop T, Franceschi C, Hirokawa K, Pawelec G (eds) In Handbook on Immunosenescence. Springer, Netherlands, pp 533–546

    Google Scholar 

  • Tomasec P, Wang EC, Davison AJ, Vojtesek B, Armstrong M, Griffin C, McSharry BP, Morris RJ, Llewellyn-Lacey S, Rickards C, Nomoto A, Sinzger C, Wilkinson GW (2005) Downregulation of natural killer cell-activating ligand CD155 by human cytomegalovirus UL141. Nat Immunol 6:181–188

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Vacca P, Martini S, Garelli V, Passalacqua G, Moretta L, Mingari MC (2013) NK cells from malignant pleural effusions are not anergic but produce cytokines and display strong antitumor activity on short-term IL-2 activation. Eur J Immunol 43:550–561

    Article  CAS  PubMed  Google Scholar 

  • Wikby A, Ferguson F, Forsey R, Thompson J, Strindhall J, Lofgren S, Nilsson BO, Ernerudh J, Pawelec G, Johansson B (2005) An immune risk phenotype, cognitive impairment, and survival in very late life: impact of allostatic load in Swedish octogenarian and nonagenarian humans. J Gerontol A 60:556–565

    Article  Google Scholar 

  • Wu Z, Sinzger C, Frascaroli G, Reichel J, Bayer C, Wang L, Schirmbeck R, Mertens T (2013) Human cytomegalovirus-induced NKG2C(hi) CD57(hi) natural killer cells are effectors dependent on humoral antiviral immunity. J Virol 87:7717–7725

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhang Y, Wallace DL, de Lara CM, Ghattas H, Asquith B, Worth A, Griffin GE, Taylor GP, Tough DF, Beverley PC, Macallan DC (2007) In vivo kinetics of human natural killer cells: the effects of ageing and acute and chronic viral infection. Immunology 121:258–265

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zwirner NW, Domaica CI (2010) Cytokine regulation of natural killer cell effector functions. BioFactors 36:274–288

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants PS09/00723 and PI13/02691 (to R.S.) from Spanish Ministry of Health, SAF2009-09711 and SAF2013-46161-R (to RT) from the Ministry of Science and Innovation of Spain and grants from Junta de Andalucia (to R.S.) and to INPATT research group from Junta de Extremadura (GRU10104) and from University of Extremadura (to RT) co-financed by European Regional Development Fund (FEDER).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rafael Solana.

Additional information

Rafael Solana and Raquel Tarazona are co-senior authors with similar contribution to the manuscript

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (TIFF 390 kb)

Supplementary material 2 (DOC 36 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Campos, C., López, N., Pera, A. et al. Expression of NKp30, NKp46 and DNAM-1 activating receptors on resting and IL-2 activated NK cells from healthy donors according to CMV-serostatus and age. Biogerontology 16, 671–683 (2015). https://doi.org/10.1007/s10522-015-9581-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10522-015-9581-0

Keywords

Navigation