Abstract
Immunological memory is at the core of protective mechanisms against microbial pathogens and possibly of defenses against tumors. Here, a new perspective is offered on the qualitative and quantitative aspects of the T cell response as it relates to protection. Two main points are proposed. First, the conditions of the initial immune response (priming) are critically important in the induction of T cell memory and protection. Second, at the present time, protection against microbial pathogens appears to correlate with the function of central memory T cells. A series of considerations and suggestions are being made for new ways to optimize the induction of protective T cell responses by vaccination both in the immunologically naive and experienced individual; emphasis is placed on: dose of antigen, the availability of T cell help, avoidance of overt inflammatory conditions and efforts to decelerate cellular senescence in responding T cells.
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References
Diamond J. Guns, germs and steel: the fates of human societies. W.W. Norton & Company; 1997
Thucydides. (431 BC) History of the Pelopponesian War
Celsus AC (c.30AD) De Medicina. Book V (23:3)
Zanetti M, et al. The immunology of new generation vaccines. Immunol Today 1987;8:18–25
Veiga-Fernandes H, et al. Response of naive and memory CD8+ T cells to antigen stimulation in␣vivo. Nat Immunol 2000;1:47–53
Plotkin S, Orenstein W. Vaccines. W.B. Saunders Co.; 2004
Edghill-Smith Y, et al. Smallpox vaccine-induced antibodies are necessary and sufficient for protection against monkeypox virus. Nat Med 2005;11:740–7
Salk J, Salk D. Control of influenza and poliomyelitis with killed virus vaccines. Science 1977;195(4281):834–47
Kilbourne E, Arden N. Inactivated influenza vaccines. In: Plotkin S, Orenstein W, editors. Vaccines. W.B. Saunders Co; 1999. p. 531–552
Salk J, Zanetti M. Next step in the evolution of vaccinology. In: Talwar editor. Progress in vaccingoloy. Vol. 2. Springer-Verlag; 1989
Panum PL. Beobachtungen uber das masernacontagium. Virchows Arch 1847;1:492–503
Sawyer W. Persistence of yellow fever immunity. J Prevent Med 1930;(5):413–28
Paul JR, et al. Antibodies to three different antigenic types of poliomyelitis virus in sera from north Alaskan Eskimos. Am J Hyg 1951;54:275–85
Crotty S, et al. Cutting edge: long-term B cell memory in humans after smallpox vaccination. J␣Immunol 2003;171:4969–73
Burnet F. The clonal selection theory of acquired immunity. Cambridge University Press; 1959
Zinkernagel RM, Hengartner H. Regulation of the immune response by antigen. Science 2001;293:251–3
Unanue ER. Perspective on antigen processing and presentation. Immunol Rev 2002;185:86–102
Paul WE, Seder RA. Lymphocyte responses and cytokines. Cell 1994;76(2):241–51
Bluestone JA, et al. Accessory molecules. In: Paul WE editor. Fundamental immunology. 4th ed. Raven Press; 1999. p. 449–78
Zinkernagel RM, et al. Antigen localisation regulates immune responses in a dose- and time-dependent fashion: a geographical view of immune reactivity. Immunol Rev 1997;156:199–209
Zanetti M, et al. B lymphocytes as APC based genetic vaccines. Immunol Rev 2004;199:264–78
Zinkernagel RM. What is missing in immunology to understand immunity? Nat Immunol 2000;1:181–5
Murali-Krishna K, et al. Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 1998;8:177–87
Schluns KS, Lefrancois L. Cytokine control of memory T-cell development and survival. Nat Rev Immunol 2003;3:269–79
Badovinac VP, et al. Accelerated CD8+ T-cell memory and prime-boost response after dendritic-cell vaccination. Nat Med 2005;11:748–56
Kaech SM, et al. Molecular and functional profiling of memory CD8 T cell differentiation. Cell 2002;111:837–51
Kaech SM, Ahmed R. Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naive cells. Nat Immunol 2001;2:415–22
Mercado R, et al. Early programming of T cell populations responding to bacterial infection. J Immunol 2000;165:6833–9
Badovinac VP, et al. Programmed contraction of CD8(+) T cells after infection. Nat Immunol 2002;3:619–26
Tanchot C, et al. Lymphocyte homeostasis. Semin Immunol 1997;9:331–7
Jameson SC. Maintaining the norm: T-cell homeostasis. Nat Rev Immunol 2002;2:547–56
Schluns KS, et al. Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in␣vivo. Nat Immunol 2000;1(5):426–32
Tan JT, et al. Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells. J Exp Med 2002;195:1523–32
Goldrath AW, et al. Cytokine requirements for acute and basal homeostatic proliferation of naive and memory CD8+ T cells. J Exp Med 2002;195:1515–22
Huang LR, et al. Potent induction of long-term CD8+ T cell memory by short-term IL-4 exposure during T cell receptor stimulation. Proc Natl Acad Sci USA 2000;97:3406–11
Williams MA, et al. Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature 2006;441:890–3
Tanchot C, et al. Differential requirements for survival and proliferation of CD8 naive or memory T cells. Science 1997;276:2057–62
Scheller LF, Azad AF. Maintenance of protective immunity against malaria by persistent hepatic parasites derived from irradiated sporozoites. Proc Natl Acad Sci USA 1995;92:4066–8
Polic B, et al. How alpha beta T cells deal with induced TCR alpha ablation. Proc Natl Acad Sci USA 2001;98:8744–9
Min B, et al. Neonates support lymphopenia-induced proliferation. Immunity 2003;18:131–40
Prlic M, et al. Homeostatic expansion occurs independently of costimulatory signals. J Immunol 2001;167:5664–8
Zanetti M, Franchini G. T cell memory and protective immunity by vaccination. Is more better? Trends Immunol 2006 Nov;27(11):511–7
Bevan MJ, Fink PJ. The CD8 response on autopilot. Nat Immunol 2001;2:381–2
Uzonna JE, et al. Immune elimination of Leishmania major in mice: implications for immune memory, vaccination, and reactivation disease. J Immunol 2001;167:6967–74
Dudani R, et al. Multiple mechanisms compensate to enhance tumor-protective CD8(+) T cell response in the long-term despite poor CD8(+) T cell priming initially: comparison between an acute versus a chronic intracellular bacterium expressing a model antigen. J Immunol 2002;168:5737–45
Kundig TM, et al. On T cell memory: arguments for antigen dependence. Immunol Rev 1996;150:63–90
Janssen EM, et al. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 2003;421:852–6
Sun JC, Bevan MJ. Defective CD8 T cell memory following acute infection without CD4 T cell help. Science 2003;300:339–42
Sun JC, et al. CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection. Nat Immunol 2004;5:927–33
Wang JC, Livingstone AM. Cutting edge: CD4+ T cell help can be essential for primary CD8+ T cell responses in␣vivo. J Immunol 2003;171:6339–43
Shedlock DJ, Shen H. Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 2003;300:337–9
Langlade-Demoyen P, et al. Role of T cell help and endoplasmic reticulum targeting in protective CTL response against influenza virus. Eur J Immunol 2003;33:720–8
Janssen EM, et al. CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death. Nature 2005;434:88–93
Hamilton SE, et al. The generation of protective memory-like CD8+ T cells during homeostatic proliferation requires CD4+ T cells. Nat Immunol 2006;7:475–81
Parish CR. Immune response to chemically modified flagellin. II. Evidence for a fundamental relationship between humoral and cell-mediated immunity. J Exp Med 1971;134:21–47
Hosken NA, et al. The effect of antigen dose on CD4+ T helper cell phenotype development in a T cell receptor-alpha beta-transgenic model. J Exp Med 1995;182:1579–84
Gallimore A, et al. Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes. J Exp Med 1998;187:1383–93
Hayflick L. The limited in␣vitro lifetime of human diploid cell strains. Exp Cell Res 1965;37:614–36
Akbar AN, et al. Will telomere erosion lead to a loss of T-cell memory? Nat Rev Immunol 2004;4:737–43
Ouyang Q, et al. Dysfunctional CMV-specific CD8(+) T cells accumulate in the elderly. Exp Gerontol 2004;39:607–13
Brenchley JM, et al. Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Blood 2003;101:2711–20
Ibegbu CC, et al. 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 2005;174:6088–94
Papagno L, et al. Immune activation and CD8+ T-cell differentiation towards senescence in HIV-1 infection. PLoS Biol 2004;2:E20
Pope C, et al. Organ-specific regulation of the CD8 T cell response to Listeria monocytogenes infection. J Immunol 2001;166:3402–9
Castiglioni P, et al. Genetically programmed B lymphocytes are highly efficient in inducing anti-virus protective immunity by central memory CD8 T cells. Vaccine 2004;23:699–708
Hel Z, et al. Containment of simian immunodeficiency virus infection in vaccinated macaques: correlation with the magnitude of virus-specific pre- and postchallenge CD4+ and CD8+ T cell responses. J␣Immunol 2002;169:4778–87
Hel Z, et al. A novel chimeric Rev, Tat, and Nef (Retanef) antigen as a component of an SIV/HIV vaccine. Vaccine 2002;20:3171–86
Sallusto F, et al. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 1999;401:708–12
Masopust D, et al. Preferential localization of effector memory cells in nonlymphoid tissue. Science 2001;291:2413–7
Kaech SM, et al. Effector and memory T-cell differentiation: implications for vaccine development. Nat Rev Immunol 2002;2:251–62
Wherry EJ, et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat Immunol 2003;4:225–34
Barber DL, et al. Cutting edge: rapid in␣vivo killing by memory CD8 T cells. J Immunol 2003;171:27–31
Vaccari M, et al. Vaccine-induced CD8+ central memory T cells in protection from simian AIDS. J␣Immunol 2005;175:3502–7
et al. Central memory T cells mediate long-term immunity to Leishmania major in the absence of persistent parasites. Nat Med 2004;10:1104–10
Klebanoff CA, et al. Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc Natl Acad Sci USA 2005;102:9571–6
Hogan RJ, et al. Long-term maintenance of virus-specific effector memory CD8+ T cells in the lung airways depends on proliferation. J Immunol 2002;169:4976–81
Bachmann MF, et al. Recall proliferation potential of memory CD8+ T Cells and antiviral protection. J␣Immunol 2005;175:4677–85
Wherry EJ, et al. Low CD8 T-cell proliferative potential and high viral load limit the effectiveness of therapeutic vaccination. J Virol 2005;79(14):8960–8
Fuller MJ, et al. Cutting edge: emergence of CD127high functionally competent memory T cells is compromised by high viral loads and inadequate T cell help. J Immunol 2005;174:5926–30
Mazo IB, et al. Bone marrow is a major reservoir and site of recruitment for central memory CD8+ T cells. Immunity 2005;22:259–70
Becker TC, et al. Bone marrow is a preferred site for homeostatic proliferation of memory CD8 T cells. J Immunol 2005;174:1269–73
Parretta E, et al. CD8 cell division maintaining cytotoxic memory occurs predominantly in the bone marrow. J Immunol 2005;174:7654–64
Effros RB. Replicative senescence of CD8 T cells: effect on human ageing. Exp Gerontol 2004;39:517–24
Yotnda P, et al. Cytotoxic T cell response against the chimeric ETV6-AML1 protein in childhood acute lymphoblastic leukemia. J Clin Invest 1998;102:455–62
Cavanagh LL, et al. Activation of bone marrow-resident memory T cells by circulating, antigen-bearing dendritic cells. Nat Immunol 2005;6:1029–37
Feuerer M, et al. Therapy of human tumors in NOD/SCID mice with patient-derived reactivated memory T cells from bone marrow. Nat Med 2001;7:452–8
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This work was supported by National Institutes of Health (NIH) grants AI062894 and CA092119.
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Presented at the First Robert A Good Society Symposium, St. Perersburg, FL 2006.
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Zanetti, M. Immunity and protection, the unfolding of a tale. Immunol Res 38, 305–318 (2007). https://doi.org/10.1007/s12026-007-0005-3
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DOI: https://doi.org/10.1007/s12026-007-0005-3