Abstract
Primary human cytomegalovirus (HCMV) infection of an immunocompetent individual leads to the generation of a robust CD4+ and CD8+ T cell response which subsequently controls viral replication. HCMV is never cleared from the host and enters into latency with periodic reactivation and viral replication, which is controlled by reactivation of the memory T cells. In this article, we discuss the magnitude, phenotype and clonality of the T cell response following primary HCMV infection, the selection of responding T cells into the long-term memory pool and maintenance of this memory T cell population in the face of a latent/persistent infection. The article also considers the effect that this long-term surveillance of HCMV has on the T cell memory phenotype, their differentiation, function and the associated concepts of T cell memory inflation and immunosenescence.
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Kaech SM, Hemby S, Kersh E, Ahmed R (2002) Molecular and functional prolfiling of memory CD8 T cell differentiation. Cell 111:837–851
Kalia V, Sarkar S, Gourley TS, Rouse BT, Ahmed R (2006) Differentiation of memory B and T cells. Curr Opin Immunol 18(3):255–264
Borysiewicz LK, Morris S, Page JD, Sissons JG (1983) Human cytomegalovirus-specific cytotoxic T lymphocytes: requirements for in vitro generation and specificity. Eur J Immunol 13(10):804–809
Borysiewicz LK, Hickling JK, Graham S, Sinclair J, Cranage MP, Smith GL, Sissons JG (1988) Human cytomegalovirus-specific cytotoxic T cells. Relative frequency of stage-specific CTL recognizing the 72-kD immediate early protein and glycoprotein B expressed by recombinant vaccinia viruses. J Exp Med 168(3):919–931
McLaughlin Taylor E, Pande H, Forman SJ, Tanamachi B, Li CR, Zaia JA, Greenberg PD, Riddell SR (1994) Identification of the major late human cytomegalovirus matrix protein pp65 as a target antigen for CD8+ virus-specific cytotoxic T lymphocytes. J Med Virol 43(1):103–110 issn: 0146–6615
Wills MR, Carmichael AJ, Sissons JGP (2006) Adaptive cellular immunity to human cytomegalovirus. In: Reddehase MJ (eds) Cytomegaloviruses: molecular biology and immunology. Caister Academic press, Wymondham, pp 341–366
Boppana SB, Britt WJ (1996) Recognition of human cytomegalovirus gene products by HCMV-specific cytotoxic T cells. Virology 222(1):293–296
Kern F, Surel IP, Brock C, Freistedt B, Radtke H, Scheffold A, Blasczyk R, Reinke P, Schneider-Mergener J, Radbruch A, Walden P, Volk HD (1998) T-cell epitope mapping by flow cytometry. Nat Med 4(8):975–978
Wills MR, Carmichael AJ, Mynard K, Jin X, Weekes MP, Plachter B, Sissons JG (1996) The human cytotoxic T-lymphocyte (CTL) response to cytomegalovirus is dominated by structural protein pp65: frequency, specificity, and T-cell receptor usage of pp65-specific CTL. J Virol 70(11):7569–7579
Sylwester AW, Mitchell BL, Edgar JB, Taormina C, Pelte C, Ruchti F, Sleath PR, Grabstein KH, Hosken NA, Kern F, Nelson JA, Picker LJ (2005) Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med 202(5):673–685
Davrinche C (2006) Combat between cytomegalovirus and dendritic cells in T-cell priming. In: M.J. Reddehase (Eds) Cytomegaloviruses: molecular biology and immunology. Caister Academic press, Wymondham, pp 367–382
Arrode G, Boccaccio C, Lule J, Allart S, Moinard N, Abastado JP, Alam A, Davrinche C (2000) Incoming human cytomegalovirus pp65 (UL83) contained in apoptotic infected fibroblasts is cross-presented to CD8(+) T cells by dendritic cells. J Virol 74(21):10018–10024
Tabi Z, Moutaftsi M, Borysiewicz LK (2001) Human cytomegalovirus pp65- and immediate early 1 antigen-specific HLA class I-restricted cytotoxic T cell responses induced by cross-presentation of viral antigens. J Immunol 166(9):5695–5703
Weekes MP, Wills MR, Mynard K, Carmichael AJ, Sissons JG (1999) The memory cytotoxic T-lymphocyte (CTL) response to human cytomegalovirus infection contains individual peptide-specific CTL clones that have undergone extensive expansion in vivo. J Virol 73(3):2099–2108
Khan N, Cobbold M, Keenan R, Moss PA (2002) Comparative analysis of CD8+ T cell responses against human cytomegalovirus proteins pp65 and immediate early 1 shows similarities in precursor frequency, oligoclonality, and phenotype. J Infect Dis 185(8):1025–1034
Khan N, Shariff N, Cobbold M, Bruton R, Ainsworth JA, Sinclair AJ, Nayak L, Moss PA (2002) Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J Immunol 169(4):1984–1992
Wills MR, Carmichael AJ, Weekes MP, Mynard K, Okecha G, Hicks R, Sissons JG (1999) Human virus-specific CD8+ CTL clones revert from CD45ROhigh to CD45RAhigh in vivo: CD45RAhighCD8+ T cells comprise both naive and memory cells. J Immunol 162(12):7080–7087
Wills MR, Okecha G, Weekes MP, Gandhi MK, Sissons PJ, Carmichael AJ (2002) Identification of naive or antigen-experienced human CD8(+) T cells by expression of costimulation and chemokine receptors: analysis of the human cytomegalovirus-specific CD8(+) T cell response. J Immunol 168(11):5455–5464
Gillespie GM, Wills MR, Appay V, O’Callaghan C, Murphy M, Smith N, Sissons P, Rowland-Jones S, Bell JI, Moss PA (2000) Functional heterogeneity and high frequencies of cytomegalovirus-specific CD8(+) T lymphocytes in healthy seropositive donors. J Virol 74(17):8140–8150
Riddell SR, Watanabe KS, Goodrich JM, Li CR, Agha ME, Greenberg PD (1992) Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. Science 257(5067):238–241
Peggs KS, Verfuerth S, Pizzey A, Khan N, Guiver M, Moss PA, Mackinnon S (2003) Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines. Lancet 362(9393):1375–1377
Walter EA, Greenberg PD, Gilbert MJ, Finch RJ, Watanabe KS, Thomas ED, Riddell SR (1995) Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med 333(16):1038–1044
Cwynarski K, Ainsworth J, Cobbold M, Wagner S, Mahendra P, Apperley J, Goldman J, Craddock C, Moss PA (2001) Direct visualization of cytomegalovirus-specific T-cell reconstitution after allogeneic stem cell transplantation. Blood 97(5):1232–1240
Einsele H, Roosnek E, Rufer N, Sinzger C, Riegler S, Loffler J, Grigoleit U, Moris A, Rammensee HG, Kanz L, Kleihauer A, Frank F, Jahn G, Hebart H (2002) Infusion of cytomegalovirus (CMV)-specific T cells for the treatment of CMV infection not responding to antiviral chemotherapy. Blood 99(11):3916–3922
Reddehase MJ, Mutter W, Munch K, Buhring HJ, Koszinowski UH (1987) CD8-positive T lymphocytes specific for murine cytomegalovirus immediate-early antigens mediate protective immunity. J Virol 61(10):3102–3108
Podlech J, Holtappels R, Pahl-Seibert MF, Steffens HP, Reddehase MJ (2000) Murine model of interstitial cytomegalovirus pneumonia in syngeneic bone marrow transplantation: persistence of protective pulmonary CD8-T-cell infiltrates after clearance of acute infection. J Virol 74(16):7496–7507
Polic B, Hengel H, Krmpotic A, Trgovcich J, Pavic I, Luccaronin P, Jonjic S, Koszinowski UH (1998) Hierarchical and redundant lymphocyte subset control precludes cytomegalovirus replication during latent infection. J Exp Med 188(6):1047–1054
Barnes PD, Grundy JE (1992) Down-regulation of the class I HLA heterodimer and beta 2-microglobulin on the surface of cells infected with cytomegalovirus. J Gen Virol 73(Pt 9):2395–2403
Wiertz EJ, Tortorella D, Bogyo M, Yu J, Mothes W, Jones TR, Rapoport TA, Ploegh HL (1996) Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction [see comments]. Nature 384(6608):432–438
Wiertz EJ, Jones TR, Sun L, Bogyo M, Geuze HJ, Ploegh HL (1996) The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol. Cell 84(5):769–779
Jones TR, Hanson LK, Sun L, Slater JS, Stenberg RM, Campbell AE (1995) Multiple independent loci within the human cytomegalovirus unique short region down-regulate expression of major histocompatibility complex class I heavy chains. J Virol 69(8):4830–4841
Jones TR, Wiertz EJ, Sun L, Fish KN, Nelson JA, Ploegh HL (1996) Human cytomegalovirus US3 impairs transport and maturation of major histocompatibility complex class I heavy chains. Proc Natl Acad Sci USA 93(21):11327–11333
Lehner PJ, Karttunen JT, Wilkinson GW, Cresswell P (1997) The human cytomegalovirus US6 glycoprotein inhibits transporter associated with antigen processing-dependent peptide translocation. Proc Natl Acad Sci USA 94(13):6904–6909
Ahn K, Gruhler A, Galocha B, Jones TR, Wiertz EJ, Ploegh HL, Peterson PA, Yang Y, Fruh K (1997) The ER-luminal domain of the HCMV glycoprotein US6 inhibits peptide translocation by TAP. Immunity 6(5):613–621
Gold MC, Munks MW, Wagner M, McMahon CW, Kelly A, Kavanagh DG, Slifka MK, Koszinowski UH, Raulet DH, Hill AB (2004) Murine cytomegalovirus interference with antigen presentation has little effect on the size or the effector memory phenotype of the CD8 T cell response. J Immunol 172(11):6944–6953
Khan N, Bruton R, Taylor GS, Cobbold M, Jones TR, Rickinson AB, Moss PA (2005) Identification of cytomegalovirus-specific cytotoxic T lymphocytes in vitro is greatly enhanced by the use of recombinant virus lacking the US2 to US11 region or modified vaccinia virus Ankara expressing individual viral genes. J Virol 79(5):2869–2879
Holtappels R, Podlech J, Pahl-Seibert MF, Julch M, Thomas D, Simon CO, Wagner M, Reddehase MJ (2004) Cytomegalovirus misleads its host by priming of CD8 T cells specific for an epitope not presented in infected tissues. J Exp Med 199(1):131–136
Kern F, Surel IP, Faulhaber N, Frommel C, Schneider-Mergener J, Schonemann C, Reinke P, Volk HD (1999) Target structures of the CD8(+)-T-cell response to human cytomegalovirus: the 72-kilodalton major immediate-early protein revisited. J Virol 73(10):8179–8184
Besold K, Frankenberg N, Pepperl-Klindworth S, Kuball J, Theobald M, Hahn G, Plachter B (2007) Processing and MHC class I presentation of human cytomegalovirus pp65-derived peptides persist despite gpUS2–11-mediated immune evasion. J Gen Virol 88(Pt 5):1429–1439
Manley TJ, Luy L, Jones T, Boeckh M, Mutimer H, Riddell SR (2004) Immune evasion proteins of human cytomegalovirus do not prevent a diverse CD8+ cytotoxic T-cell response in natural infection. Blood 104(4):1075–1082
Gamadia LE, Remmerswaal EB, Weel JF, Bemelman F, van Lier RA, Ten Berge IJ (2003) Primary immune responses to human CMV: a critical role for IFN-gamma-producing CD4+ T cells in protection against CMV disease. Blood 101(7):2686–2692
Reddehase MJ, Jonjic S, Weiland F, Mutter W, Koszinowski UH (1988) Adoptive immunotherapy of murine cytomegalo-virus adrenalitis in the immunocompromised host: Cd4-helper-independent antiviral function of Cd8-positive memory lymphocytes-T derived from latently infected donors. J Virol 62(3):1061–1065
Kern F, Bunde T, Faulhaber N, Kiecker F, Khatamzas E, Rudawski IM, Pruss A, Gratama JW, Volkmer-Engert R, Ewert R, Reinke P, Volk HD, Picker LJ (2002) Cytomegalovirus (CMV) phosphoprotein 65 makes a large contribution to shaping the T cell repertoire in CMV-exposed individuals. J Infect Dis 185(12):1709–1716
Davignon JL, Clement D, Alriquet J, Michelson S, Davrinche C (1995) Analysis of the proliferative T cell response to human cytomegalovirus major immediate-early protein (IE1): phenotype, frequency and variability. Scand J Immunol 41(3):247–255
Beninga J, Kropff B, Mach M (1995) Comparative analysis of fourteen individual human cytomegalovirus proteins for helper T cell response. J Gen Virol 76(Pt 1):153–160
Davignon JL, Castanie P, Yorke JA, Gautier N, Clement D, Davrinche C (1996) Anti-human cytomegalovirus activity of cytokines produced by CD4+ T-cell clones specifically activated by IE1 peptides in vitro. J Virol 70(4):2162–2169
Elkington R, Shoukry NH, Walker S, Crough T, Fazou C, Kaur A, Walker CM, Khanna R (2004) Cross-reactive recognition of human and primate cytomegalovirus sequences by human CD4 cytotoxic T lymphocytes specific for glycoprotein B and H. Eur J Immunol 34(11):3216–3226
Weekes MP, Wills MR, Sissons JG, Carmichael AJ (2004) Long-term stable expanded human CD4+ T cell clones specific for human cytomegalovirus are distributed in both CD45RAhigh and CD45ROhigh populations. J Immunol 173(9):5843–5851
Bitmansour AD, Douek DC, Maino VC, Picker LJ (2002) Direct ex vivo analysis of human CD4(+) memory T cell activation requirements at the single clonotype level. J Immunol 169(3):1207–1218
Rentenaar RJ, Gamadia LE, van DerHoek N, van Diepen FN, Boom R, Weel JF, Wertheim-van Dillen PM, van Lier RA, ten Berge IJ (2000) Development of virus-specific CD4(+) T cells during primary cytomegalovirus infection. J Clin Invest 105(4):541–548
van Leeuwen EM, Remmerswaal EB, Vossen MT, Rowshani AT, Wertheim -van Dillen PM, van Lier RA, ten Berge IJ (2004) Emergence of a CD4+CD28− granzyme B+, cytomegalovirus-specific T cell subset after recovery of primary cytomegalovirus infection. J Immunol 173(3):1834–1841
Miller DM, Cebulla CM, Rahill BM, Sedmak DD (2001) Cytomegalovirus and transcriptional down-regulation of major histocompatibility complex class II expression. Semin Immunol 13(1):11–18
Kuijpers TW, Vossen MT, Gent MR, Davin JC, Roos MT, Wertheim-van Dillen PM, Weel JF, Baars PA, van Lier RA (2003) Frequencies of circulating cytolytic, CD45RA+CD27−, CD8+ T lymphocytes depend on infection with CMV. J Immunol 170(8):4342–4348
van Leeuwen EM, Gamadia LE, Baars PA, Remmerswaal EB, ten Berge IJ, van Lier RA (2002) Proliferation requirements of cytomegalovirus-specific, effector-type human CD8+ T cells. J Immunol 169(10):5838–5843
van Leeuwen E, van Buul JD, Remmerswaal EBM, Hordijk PL, ten Berge IJ, van Lier RA (2005) Functional re-expression of CCR7 on CMV-specific CD8+ T cells upon antigenic stimulation. Int Immunol 17:713–719
Appay V, Dunbar PR, Callan M, Klenerman P, Gillespie GM, Papagno L, Ogg GS, King A, Lechner F, Spina CA, Little S, Havlir DV, Richman DD, Gruener N, Pape G, Waters A, Easterbrook P, Salio M, Cerundolo V, McMichael AJ, Rowland-Jones SL (2002) Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat Med 8(4):379–85
Kern F, Khatamzas E, Surel I, Frommel C, Reinke P, Waldrop SL, Picker LJ, Volk HD (1999) Distribution of human CMV-specific memory T cells among the CD8pos. Subsets defined by CD57, CD27, and CD45 isoforms. Eur J Immunol 29(9):2908–2915
Brenchley JM, Karandikar NJ, Betts MR, Ambrozak DR, Hill BJ, Crotty LE, Casazza JP, Kuruppu J, Migueles SA, Connors M, Roederer M, Douek DC, Koup RA (2003) Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Blood 101(7):2711–2720
Pittet MJ, Speiser DE, Valmori D, Cerottini JC, Romero P (2000) Cutting edge: cytolytic effector function in human circulating CD8+ T cells closely correlates with CD56 surface expression. J Immunol 164(3):1148–1152
Speiser DE, Colonna M, Ayyoub M, Cella M, Pittet MJ, Batard P, Valmori D, Guillaume P, Lienard D, Cerottini JC, Romero P (2001) The activatory receptor 2B4 is expressed in vivo by human CD8+ effector alpha beta T cells. J Immunol 167(11):6165–6170
Voehringer D, Koschella M, Pircher H (2002) Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1). Blood 100(10):3698–3702
Ibegbu CC, Xu YX, Harris W, Maggio D, Miller JD, Kourtis AP (2005) Expression of killer cell lectin-like receptor G1 on antigen-specific human CD8+ T lymphocytes during active, latent, and resolved infection and its relation with CD57. J Immunol 174(10):6088–6094
Northfield J, Lucas M, Jones H, Young NT, Klenerman P (2005) Does memory improve with age? CD85j (ILT-2/LIR-1) expression on CD8+ T cells correlates with “memory inflation” in human cytomegalovirus infection. Immunol Cell Biol 83:182–188
Antrobus RD, Khan N, Hislop AD, Montamat D-Sicotte, Garner LI, Rickinson AB, Moss PA, Willcox BE (2005) Virus-specific cytotoxic T lymphocytes differentially express cell-surface leukocyte immunoglobulin-like receptor-1, an inhibitory receptor for class I major histocompatibility complex molecules. J Infect Dis 191(11):1842–1853
Gandhi MK, Wills MR, Okecha G, Day EK, Hicks R, Marcus RE, Sissons JG, Carmichael AJ (2003) Late diversification in the clonal composition of human cytomegalovirus-specific CD8+ T cells following allogeneic hemopoietic stem cell transplantation. Blood 102(9):3427–3438
van Leeuwen EM, Koning JJ, Remmerswaal EB, van Baarle D, van Lier RA, ten Berge IJ (2006) Differential usage of cellular niches by cytomegalovirus versus EBV- and influenza virus-specific CD8+ T cells. J Immunol 177(8):4998–5005
Hamann D, Baars PA, Rep MH, Hooibrink B, Kerkhof-Garde SR, Klein MR, van Lier RA (1997) Phenotypic and functional separation of memory and effector human CD8+ T cells. J Exp Med 186(9):1407–1418
Chan KS, Kaur A (2007) Flow cytometric detection of degranulation reveals phenotypic heterogeneity of degranulating CMV-specific CD8+ T lymphocytes in rhesus macaques. J Immunol Methods 325(1–2):20–34
Vallejo AN (2005) CD28 extinction in human T cells: altered functions and the program of T-cell senescence. Immunol Rev 205:158–169
Azuma M, Phillips JH, Lanier LL (1993) CD28− T lymphocytes. Antigenic and functional properties. J Immunol 150(4):1147–1159
Posnett DN, Edinger JW, Manavalan JS, Irwin C, Marodon G (1999) Differentiation of human CD8 T cells: implications for in vivo persistence of CD8+ CD28− cytotoxic effector clones. Int Immunol 11(2):229–241
Fagnoni FF, Vescovini R, Mazzola M, Bologna G, Nigro E, Lavagetto G, Franceschi C, Passeri M, Sansoni P (1996) Expansion of cytotoxic CD8+ CD28− T cells in healthy ageing people, including centenarians. Immunology 88(4):501–507
Effros RB, Boucher N, Porter V, Zhu X, Spaulding C, Walford RL, Kronenberg M, Cohen D, Schachter F (1994) Decline in CD28+ T cells in centenarians and in long-term T cell cultures: a possible cause for both in vivo and in vitro immunosenescence. Exp Gerontol 29(6):601–609
Effros RB, Allsopp R, Chiu CP, Hausner MA, Hirji K, Wang L, Harley CB, Villeponteau B, West MD, Giorgi JV (1996) Shortened telomeres in the expanded CD28−CD8+ cell subset in HIV disease implicate replicative senescence in HIV pathogenesis. Aids 10(8):F17–F22
Hazzan M, Labalette M, Noel C, Lelievre G, Dessaint JP (1997) Recall response to cytomegalovirus in allograft recipients: mobilization of CD57+, CD28+ cells before expansion of CD57+, CD28− cells within the CD8+ T lymphocyte compartment. Transplantation 63(5):693–698
Weekes MP, Carmichael AJ, Wills MR, Mynard K, Sissons JG (1999) Human CD28−CD8+ T cells contain greatly expanded functional virus-specific memory CTL clones. J Immunol 162(12):7569–7577
Day EK, Carmichael AJ, Ten Berge IJ, Waller EC, Sissons JG, Wills MR (2007) Rapid CD8+ T Cell repertoire focusing and selection of high-affinity clones into memory following primary infection with a persistent human virus: human cytomegalovirus. J Immunol 179(5):3203–3213
van Leeuwen EM, de Bree GJ, ten Berge IJ, van Lier RA (2006) Human virus-specific CD8+ T cells: diversity specialists. Immunol Rev 211:225–235
Marchant A, Appay V, Van Der Sande M, Dulphy N, Liesnard C, Kidd M, Kaye S, Ojuola O, Gillespie GM, Vargas Cuero AL, Cerundolo V, Callan M, McAdam KP, Rowland-Jones SL, Donner C, McMichael AJ, Whittle H (2003) Mature CD8(+) T lymphocyte response to viral infection during fetal life. J Clin Invest 111(11):1747–1755
Miles DJ, vander Sande M, Jeffries D, Kaye S, Ismaili J, Ojuola O, Sanneh M, Touray ES, Waight P, Rowland-Jones S, Whittle H, Marchant A (2007) Cytomegalovirus infection in Gambian infants leads to profound CD8 T-cell differentiation. J Virol 81(11):5766–5776
van Leeuwen EM, de Bree GJ, Remmerswaal EB, Yong SL, Tesselaar K, ten Berge IJ, van Lier RA (2005) IL-7 receptor alpha chain expression distinguishes functional subsets of virus-specific human CD8+ T cells. Blood 106(6):2091–2098
Kaech SM, Tan JT, Wherry EJ, Konieczny BT, Surh CD, Ahmed R (2003) Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat Immunol 4(12):1191–1198
Huster KM, Busch V, Schiemann M, Linkemann K, Kerksiek KM, Wagner H, Busch DH (2004) Selective expression of IL-7 receptor on memory T cells identifies early CD40L-dependent generation of distinct CD8+ memory T cell subsets. Proc Natl Acad Sci USA 101(15):5610–5615
Weekes MP, Wills MR, Mynard K, Hicks R, Sissons JG, Carmichael AJ (1999) Large clonal expansions of human virus-specific memory cytotoxic T lymphocytes within the CD57+ CD28− CD8+ T-cell population. Immunology 98(3):443–449
Sourdive DJ, Murali K Krishna, Altman JD, Zajac AJ, Whitmire JK, Pannetier C, Kourilsky P, Evavold B, Sette A, Ahmed R (1998) Conserved T cell repertoire in primary and memory CD8 T cell responses to an acute viral infection. J Exp Med 188:71–79
Blattman JN, Sourdive DJ, Murali-Krishna K, Ahmed R, Altman JD (2000) Evolution of the T cell repertoire during primary, memory, and recall responses to viral infection. J Immunol 165(11):6081–6090
Karrer U, Sierro S, Wagner M, Oxenius A, Hengel H, Koszinowski UH, Phillips RE, Klenerman P (2003) Memory inflation: continuous accumulation of antiviral CD8+ T cells over time. J Immunol 170(4):2022–2029
Pahl-Seibert MF, Juelch M, Podlech J, Thomas D, Deegen P, Reddehase MJ, Holtappels R (2005) Highly protective in vivo function of cytomegalovirus IE1 epitope-specific memory CD8 T cells purified by T-cell receptor-based cell sorting. J Virol 79(9):5400–5413
Trautmann L, Rimbert M, Echasserieau K, Saulquin X, Neveu B, Dechanet J, Cerundolo V, Bonneville M (2005) Selection of T cell clones expressing high-affinity public TCRs within human cytomegalovirus-specific CD8 T cell responses. J Immunol 175(9):6123–6132
Lawson TM, Man S, Wang ECY, Williams S, Amos N, Gillespie GM, Moss PA, Borysiewcz LK (2001) Functional differences between influenza A-specific cytotoxic T lymphocyte clones expressing dominant and subdominant TCR. Int Immunol 13(11):1383–1390
Fujii Y, Okumura M, Inada K, Nakahara K (1992) Reversal of CD45R isoform switching in CD8+ T cells. Cell Immunol 139(1):176–184
Michie CA, McLean A, Alcock C, Beverley PC (1992) Lifespan of human lymphocyte subsets defined by CD45 isoforms. Nature 360(6401):264–265
Sparshott SM, Bell EB (1994) Membrane CD45R isoform exchange on CD4 T cells is rapid, frequent and dynamic in vivo. Eur J Immunol 24(11):2573–2578
Bell EB, Sparshott SM (1990) Interconversion of CD45R subsets of CD4 T cells in vivo. Nature 348(6297):163–166
Monteiro M, Evaristo C, Legrand A, Nicoletti A, Rocha B (2007) Cartography of gene expression in CD8 single cells: novel CCR7− subsets suggest differentiation independent of CD45RA expression. Blood 109(7):2863–2870
Geginat G, Lanzavecchia A, Sallusto F (2003) Proliferation and differentiation potential of human CD8+ memory T cell subsets in response to antigen or homeostatic cytokines. Blood 101:4260–4266
Dunne PJ, Belaramani L, Fletcher JM, Fernandez S de Mattos, Lawrenz M, Soares MV, Rustin MH, Lam EW, Salmon M, Akbar AN (2005) Quiescence and functional reprogramming of Epstein-Barr virus (EBV)-specific CD8+ T cells during persistent infection. Blood 106(2):558–565
Carrasco J, Godelaine D, Van Pel A, Boon T, vander Bruggen P (2006) CD45RA on human CD8 T cells is sensitive to the time elapsed since the last antigenic stimulation. Blood 108(9):2897–2905
Borthwick NJ, Lowdell M, Salmon M, Akbar AN (2000) Loss of CD28 expression on CD8(+) T cells is induced by IL-2 receptor gamma chain signalling cytokines and type I IFN, and increases susceptibility to activation-induced apoptosis. Int Immunol 12(7):1005–1013
Kim YJ, Brutkiewicz RR, Broxmeyer HE (2002) Role of 4–1BB (CD137) in the functional activation of cord blood CD28(−)CD8(+) T cells. Blood 100(9):3253–3260
Alves NL, Arosa FA, van Lier RA (2005) IL-21 sustains CD28 expression on IL-15-activated human naive CD8+ T cells. J Immunol 175(2):755–762
Labalette M, Leteurtre E, Thumerelle C, Grutzmacher C, Tourvieille B, Dessaint JP (1999) Peripheral human CD8(+)CD28(+)T lymphocytes give rise to CD28(−)progeny, but IL-4 prevents loss of CD28 expression. Int Immunol 11(8):1327–1336
Scheuring UJ, Sabzevari H, Theofilopoulos AN (2002) Proliferative arrest and cell cycle regulation in CD8(+)CD28(−) versus CD8(+)CD28(+) T cells. Hum Immunol 63(11):1000–1009
Borthwick NJ, Bofill M, Gombert WM, Akbar AN, Medina E, Sagawa K, Lipman MC, Johnson MA, Janossy G (1994) Lymphocyte activation in HIV-1 infection. II. Functional defects of CD28− T cells. AIDS 8(4):431–441
Lewis DE, Yang L, Luo W, Wang X, Rodgers JR (1999) HIV-specific cytotoxic T lymphocyte precursors exist in a CD28−CD8+ T cell subset and increase with loss of CD4 T cells. AIDS 13(9):1029–1033
Brinchmann JE, Dobloug JH, Heger BH, Haaheim LL, Sannes M, Egeland T (1994) Expression of costimulatory molecule CD28 on T cells in human immunodeficiency virus type 1 infection: functional and clinical correlations. J Infect Dis 169(4):730–738
Vingerhoets JH, Vanham GL, Kestens LL, Penne GG, Colebunders RL, Vandenbruaene MJ, Goeman J, Gigase PL, De Boer M, Ceuppens JL (1995) Increased cytolytic T lymphocyte activity and decreased B7 responsiveness are associated with CD28 down-regulation on CD8+ T cells from HIV-infected subjects. Clin Exp Immunol 100(3):425–433
Fiorentino S, Dalod M, Olive D, Guillet JG, Gomard E (1996) Predominant involvement of CD8+CD28− lymphocytes in human immunodeficiency virus-specific cytotoxic activity. J Virol 70(3):2022–2026
Champagne P, Ogg GS, King AS, Knabenhans C, Ellefsen K, Nobile M, Appay V, Rizzardi GP, Fleury S, Lipp M, Forster R, Rowland-Jones S, Sekaly RP, McMichael AJ, Pantaleo G (2001) Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 410(6824):106–111
Dunne PJ, Faint JM, Gudgeon NH, Fletcher JM, Plunkett FJ, Soares MV, Hislop AD, Annels NE, Rickinson AB, Salmon M, Akbar AN (2002) Epstein-Barr virus-specific CD8(+) T cells that re-express CD45RA are apoptosis-resistant memory cells that retain replicative potential. Blood 100(3):933–940
Waller EC, McKinney N, Hicks R, Carmichael AJ, Sissons JG, Wills MR (2007) Differential costimulation through CD137 (4 1BB) restores proliferation of human virus-specific “effector memory” (CD28 CD45RAHI) CD8+ T cells. Blood 110(13):4360–4366
Topp MS, Riddell SR, Akatsuka Y, Jensen MC, Blattman JN, Greenberg PD (2003) Restoration of CD28 expression in CD28− CD8+ memory effector T cells reconstitutes antigen-induced IL-2 production. J Exp Med 198(6):947–955
Valenzuela HF, Effros RB (2002) Divergent telomerase and CD28 expression patterns in human CD4 and CD8 T cells following repeated encounters with the same antigenic stimulus. Clin Immunol 105(2):117–125
Monteiro J, Batliwalla F, Ostrer H, Gregersen PK (1996) Shortened telomeres in clonally expanded CD28−CD8+ T cells imply a replicative history that is distinct from their CD28+CD8+ counterparts. J Immunol 156(10):3587–3590
Weng NP, Levine BL, June CH, Hodes RJ (1995) Human naive and memory T lymphocytes differ in telomeric length and replicative potential. Proc Natl Acad Sci USA 92(24):11091–11094
Rufer N, Brummendorf TH, Kolvraa S, Bischoff C, Christensen K, Wadsworth L, Schulzer M, Lansdorp PM (1999) Telomere fluorescence measurements in granulocytes and T lymphocyte subsets point to a high turnover of hematopoietic stem cells and memory T cells in early childhood. J Exp Med 190(2):157–167
Hamann D, Kostense S, Wolthers KC, Otto SA, Baars PA, Miedema F, van Lier RA (1999) Evidence that human CD8+CD45RA+CD27− cells are induced by antigen and evolve through extensive rounds of division. Int Immunol 11(7):1027–1033
Plunkett FJ, Franzese O, Finney HM, Fletcher JM, Belaramani LL, Salmon M, Dokal I, Webster D, Lawson AD, Akbar AN (2007) The loss of telomerase activity in highly differentiated CD8+CD28−CD27− T cells is associated with decreased Akt (Ser473) phosphorylation. J Immunol 178(12):7710–7719
Holtappels R, Pahl-Seibert MF, Thomas D, Reddehase MJ (2000) Enrichment of immediate-early 1 (m123/pp89) peptide-specific CD8 T cells in a pulmonary CD62L(lo) memory-effector cell pool during latent murine cytomegalovirus infection of the lungs. J Virol 74(24):11495–11503
Holtappels R, Thomas D, Podlech J, Reddehase MJ (2002) Two antigenic peptides from genes m123 and m164 of murine cytomegalovirus quantitatively dominate CD8 T-cell memory in the H-2d haplotype. J Virol 76(1):151–164
Karrer U, Sierro S, Wagner M, Oxenius A, Hengel H, Koszinowski UH, Phillips RE, Klenerman P (2003) Memory inflation: continuous accumulation of antiviral CD8+ T cells over time. J Immunol 171(7):3895
Munks MW, Cho KS, Pinto AK, Sierro S, Klenerman P, Hill AB (2006) Four distinct patterns of memory CD8 T cell responses to chronic murine cytomegalovirus infection. J Immunol 177(1):450–458
Khan N Hislop A, Gudgeon N, Cobbold M, Khanna R, Nayak L, Rickinson AB, Moss PA (2004) Herpesvirus-specific CD8 T cell immunity in old age: cytomegalovirus impairs the response to a coresident EBV infection. J Immunol 173(12):7481–7489
Wallace DL, Zhang Y, Ghattas H, Worth A, Irvine A, Bennett AR, Griffin GE, Beverley PC, Tough DF, Macallan DC (2004) Direct measurement of T cell subset kinetics in vivo in elderly men and women. J Immunol 173(3):1787–1794
Ouyang Q, Wagner WM, Zheng W, Wikby A, Remarque EJ, Pawelec G (2004) Dysfunctional CMV-specific CD8(+) T cells accumulate in the elderly. Exp Gerontol 39(4):607–613
Ouyang Q, Wagner WM, Wikby A, Walter S, Aubert G, Dodi AI, Travers P, Pawelec G (2003) Large numbers of dysfunctional CD8+ T lymphocytes bearing receptors for a single dominant CMV epitope in the very old. J Clin Immunol 23(4):247–257
Akbar AN, Fletcher JM (2005) Memory T cell homeostasis and senescence during aging. Curr Opin Immunol 17(5):480–485
Koch S, Solana R, Dela Rosa O, Pawelec G (2006) Human cytomegalovirus infection and T cell immunosenescence: a mini review. Mech Ageing Dev 127(6):538–543
Trzonkowski P, Mysliwska J, Szmit E, Wieckiewicz J, Lukaszuk K, Brydak LB, Machala M, Mysliwski A (2003) Association between cytomegalovirus infection, enhanced proinflammatory response and low level of anti-hemagglutinins during the anti-influenza vaccination-an impact of immunosenescence. Vaccine 21(25–26):3826–3836
Saurwein-Teissl M, Lung TL, Marx F, Gschosser C, Asch E, Blasko I, Parson W, Bock G, Schonitzer D, Trannoy E, Grubeck-Loebenstein B (2002) Lack of antibody production following immunization in old age: association with CD8(+)CD28(−) T cell clonal expansions and an imbalance in the production of Th1 and Th2 cytokines. J Immunol 168(11):5893–5899
Goronzy JJ, Fulbright JW, Crowson CS, Poland GA, O’Fallon WM, Weyand CM (2001) Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals. J Virol 75(24):12182–12187
Looney RJ, Falsey A, Campbell D, Torres A, Kolassa J, Brower C, McCann R, Menegus M, McCormick K, Frampton M, Hall W, Abraham GN (1999) Role of cytomegalovirus in the T cell changes seen in elderly individuals. Clin Immunol 90(2):213–219
Wikby A, Johansson B, Olsson J, Lofgren S, Nilsson BO, Ferguson F (2002) Expansions of peripheral blood CD8 T-lymphocyte subpopulations and an association with cytomegalovirus seropositivity in the elderly: the Swedish NONA immune study. Exp Gerontol 37(2–3):445–453
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 Biol Sci Med Sci 60(5):556–565
Olsson J, Wikby A, Johansson B, Lofgren S, Nilsson BO, Ferguson FG (2000) Age-related change in peripheral blood T-lymphocyte subpopulations and cytomegalovirus infection in the very old: the Swedish longitudinal OCTO immune study. Mech Ageing Dev 121(1–3):187–201
Hadrup SR, Strindhall J, Kollgaard T, Seremet T, Johansson B, Pawelec G, thor Straten P, Wikby A (2006) Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly. J Immunol 176(4):2645–2653
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Waller, E.C.P., Day, E., Sissons, J.G.P. et al. Dynamics of T cell memory in human cytomegalovirus infection. Med Microbiol Immunol 197, 83–96 (2008). https://doi.org/10.1007/s00430-008-0082-5
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DOI: https://doi.org/10.1007/s00430-008-0082-5