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
Tóm tắt
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.
Tài liệu tham khảo
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
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
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
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
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
Bjorkstrom NK, Ljunggren HG, Sandberg JK (2010a) CD56 negative NK cells: origin, function, and role in chronic viral disease. Trends Immunol 31:401–406
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
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
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
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
Camous X, Pera A, Solana R, Larbi A (2012) NK cells in healthy aging and age-associated diseases. J Biomed Biotechnol 2012:195956
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
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
Cannon MJ, Schmid DS, Hyde TB (2010) Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol 20:202–213
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
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
Cichocki F, Miller JS, Anderson SK, Bryceson YT (2013) Epigenetic regulation of NK cell differentiation and effector functions. Front Immunol 4:55
Cooper MA, Fehniger TA, Caligiuri MA (2001) The biology of human natural killer-cell subsets. Trends Immunol 22:633–640
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
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
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
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
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
Derhovanessian E, Larbi A, Pawelec G (2009) Biomarkers of human immunosenescence: impact of Cytomegalovirus infection. Curr Opin Immunol 21:440–445
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
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
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
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
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
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
Hamerman JA, Ogasawara K, Lanier LL (2005) NK cells in innate immunity. Curr Opin Immunol 17:29–35
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
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
Lanier LL (2008) Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol 9:495–502
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
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
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
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
Marcus A, Raulet DH (2013) Evidence for natural killer cell memory. Curr Biol 23:R817–R820
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
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
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
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
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
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
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
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
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
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
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
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
Pawelec G, Derhovanessian E (2011) Role of CMV in immune senescence. Virus Res 157:175–179
Pawelec G, Akbar A, Caruso C, Solana R, Grubeck-Loebenstein B, Wikby A (2005) Human immunosenescence: is it infectious? Immunol Rev 205:257–268
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
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
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
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
Rajagopalan S, Long EO (2005) Viral evasion of NK-cell activation. Trends Immunol 26:403–405
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
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
Solana R, Mariani E (2000) NK and NK/T cells in human senescence. Vaccine 18:1613–1620
Solana R, Pawelec G, Tarazona R (2006) Aging and innate immunity. Immunity 24:491–494
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
Solana R, Campos C, Pera A, Tarazona R (2014) Shaping of NK cell subsets by aging. Curr Opin Immunol 29C:56–61
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
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
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
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
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
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
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
Zwirner NW, Domaica CI (2010) Cytokine regulation of natural killer cell effector functions. BioFactors 36:274–288