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Immunological memory ≠ protective immunity

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Abstract

So-called ‘immunological memory’ is, in my view, a typical example where a field of enquiry, i.e. to understand long-term protection to survive reexposure to infection, has been overtaken by ‘l’art pour l’art’ of ‘basic immunology’. The aim of this critical review is to point out some key differences between academic text book-defined immunological memory and protective immunity as viewed from a co-evolutionary point of view, both from the host and the infectious agents. A key conclusion is that ‘immunological memory’ of course exists, but only in particular experimental laboratory models measuring ‘quicker and better’ responses after an earlier immunization. These often do correlate with, but are not the key mechanisms of, protection. Protection depends on pre-existing neutralizing antibodies or pre-activated T cells at the time of infection—as documented by the importance of maternal antibodies around birth for survival of the offspring. Importantly, both high levels of antibodies and of activated T cells are antigen driven. This conclusion has serious implications for our thinking about vaccines and maintaining a level of protection in the population to deal with old and new infectious diseases.

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References

  1. Ahmed R, Gray D (1996) Immunological memory and protective immunity: understanding their relation. Science 272:54–60

    Article  PubMed  CAS  Google Scholar 

  2. Janeway CA, Travers P, Walport M, Shlomchik MJ (2001) Immunobiology: the immune system in health and disease, 5th edn. Garland, New York

  3. Goldsby RA, Kindt TJ, Osborne BA (2000) Kuby immunology, 4th edn. Freeman, New York

  4. Biron CA (2010) Expansion, maintenance, and memory in NK and T cells during viral infections: responding to pressures for defense and regulation. PLoS Pathog 6:e1000816

    Article  PubMed  Google Scholar 

  5. Radbruch A, Muehlinghaus G, Luger EO, Inamine A, Smith KG, Dorner T, Hiepe F (2006) Competence and competition: the challenge of becoming a long-lived plasma cell. Nat Rev Immunol 6:741–750

    Article  PubMed  CAS  Google Scholar 

  6. Zinkernagel RM (1996) Immunology taught by viruses. Science 271:173–178

    Article  PubMed  CAS  Google Scholar 

  7. Zinkernagel RM, Bachmann MF, Kundig TM, Oehen S, Pirchet H, Hengartner H (1996) On immunological memory. Annu Rev Immunol 14:333–367

    Article  PubMed  CAS  Google Scholar 

  8. Zinkernagel RM (2001) Maternal antibodies, childhood infections, and autoimmune diseases. N Engl J Med 345:1331–1335

    Article  PubMed  CAS  Google Scholar 

  9. Zinkernagel RM, Hengartner H (2004) On immunity against infections and vaccines: credo 2004. Scand J Immunol 60:9–13

    Article  PubMed  CAS  Google Scholar 

  10. Steinhoff U, Muller U, Schertler A, Hengartner H, Aguet M, Zinkernagel RM (1995) Antiviral protection by vesicular stomatitis virus-specific antibodies in alpha/beta interferon receptor-deficient mice. J Virol 69:2153–2158

    PubMed  CAS  Google Scholar 

  11. Hilleman MR (2004) Strategies and mechanisms for host and pathogen survival in acute and persistent viral infections. Proc Natl Acad Sci USA 101(Suppl 2):14560–14566

    Article  PubMed  CAS  Google Scholar 

  12. Ochsenbein AF, Fehr T, Lutz C, Suter M, Brombacher F, Hengartner H, Zinkernagel RM (1999) Control of early viral and bacterial distribution and disease by natural antibodies. Science 286:2156–2159

    Article  PubMed  CAS  Google Scholar 

  13. Fenner F (1949) Mouse-pox; infectious ectromelia of mice; a review. J Immunol 63:341–373

    PubMed  CAS  Google Scholar 

  14. Fenner F (1983) The Florey lecture, 1983. Biological control, as exemplified by smallpox eradication and myxomatosis. Proc R Soc Lond B 218:259–285

    Article  PubMed  CAS  Google Scholar 

  15. Moskophidis D, Lechner F, Pircher H, Zinkernagel RM (1993) Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 362:758–761

    Article  PubMed  CAS  Google Scholar 

  16. Ciurea A, Klenerman P, Hunziker L, Horvath E, Senn BM, Ochsenbein AF, Hengartner H, Zinkernagel RM (2000) Viral persistence in vivo through selection of neutralizing antibody-escape variants. Proc Natl Acad Sci USA 97:2749–2754

    Article  PubMed  CAS  Google Scholar 

  17. Kundig TM, Bachmann MF, Oehen S, Hoffmann UW, Simard JJ, Kalberer CP, Pircher H, Ohashi PS, Hengartner H, Zinkernagel RM (1996) On the role of antigen in maintaining cytotoxic T-cell memory. Proc Natl Acad Sci USA 93:9716–9723

    Article  PubMed  CAS  Google Scholar 

  18. Mackaness GB (1971) Resistance to intracellular infection. J Infect Dis 123:439–445

    Article  PubMed  CAS  Google Scholar 

  19. Moll H, Flohe S, Rollinghoff M (1995) Dendritic cells in Leishmania major-immune mice harbor persistent parasites and mediate an antigen-specific T cell immune response. Eur J Immunol 25:693–699

    Article  PubMed  CAS  Google Scholar 

  20. Ochsenbein AF, Pinschewer DD, Sierro S, Horvath E, Hengartner H, Zinkernagel RM (2000) Protective long-term antibody memory by antigen-driven and T help-dependent differentiation of long-lived memory B cells to short-lived plasma cells independent of secondary lymphoid organs. Proc Natl Acad Sci USA 97:13263–13268

    Article  PubMed  CAS  Google Scholar 

  21. Karrer U, Althage A, Odermatt B, Roberts CW, Korsmeyer SJ, Miyawaki S, Hengartner H, Zinkernagel RM (1997) On the key role of secondary lymphoid organs in antiviral immune responses studied in alymphoplastic (aly/aly) and spleenless (Hox11(−)/−) mutant mice. J Exp Med 185:2157–2170

    Article  PubMed  CAS  Google Scholar 

  22. Ochsenbein AF, Pinschewer DD, Odermatt B, Ciurea A, Hengartner H, Zinkernagel RM (2000) Correlation of T cell independence of antibody responses with antigen dose reaching secondary lymphoid organs: implications for splenectomized patients and vaccine design. J Immunol 164:6296–6302

    PubMed  CAS  Google Scholar 

  23. Odermatt B, Eppler M, Leist TP, Hengartner H, Zinkernagel RM (1991) Virus-triggered acquired immunodeficiency by cytotoxic T-cell-dependent destruction of antigen-presenting cells and lymph follicle structure. Proc Natl Acad Sci USA 88:8252–8256

    Article  PubMed  CAS  Google Scholar 

  24. Navarini AA, Krzyzowska M, Lang KS, Horvath E, Hengartner H, Niemialtowski MG, Zinkernagel RM (2010) Long-lasting immunity by early infection of maternal-antibody-protected infants. Eur J Immunol 40:113–116

    Article  PubMed  CAS  Google Scholar 

  25. Bachmann MF, Hengartner H, Zinkernagel RM (1995) T helper cell-independent neutralizing B cell response against vesicular stomatitis virus: role of antigen patterns in B cell induction? Eur J Immunol 25:3445–3451

    Article  PubMed  CAS  Google Scholar 

  26. Bachmann MF, Rohrer UH, Kundig TM, Burki K, Hengartner H, Zinkernagel RM (1993) The influence of antigen organization on B cell responsiveness. Science 262:1448–1451

    Article  PubMed  CAS  Google Scholar 

  27. Roden RB, Greenstone HL, Kirnbauer R, Booy FP, Jessie J, Lowy DR, Schiller JT (1996) In vitro generation and type-specific neutralization of a human papillomavirus type 16 virion pseudotype. J Virol 70:5875–5883

    PubMed  CAS  Google Scholar 

  28. Moller G (1975) One non-specific signal triggers B lymphocytes. Transpl Rev 23:126–137

    CAS  Google Scholar 

  29. Macpherson AJ, Gatto D, Sainsbury E, Harriman GR, Hengartner H, Zinkernagel RM (2000) A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 288:2222–2226

    Article  PubMed  CAS  Google Scholar 

  30. McCoy KD, Harris NL, Diener P, Hatak S, Odermatt B, Hangartner L, Senn BM, Marsland BJ, Geuking MB, Hengartner H, Macpherson AJ, Zinkernagel RM (2006) Natural IgE production in the absence of MHC Class II cognate help. Immunity 24:329–339

    Article  PubMed  CAS  Google Scholar 

  31. Pochanke V, Hatak S, Hengartner H, Zinkernagel RM, McCoy KD (2006) Induction of IgE and allergic-type responses in fur mite-infested mice. Eur J Immunol 36:2434–2445

    Article  PubMed  CAS  Google Scholar 

  32. Bos NA, Meeuwsen CG (1989) B cell repertoire in adult antigen-free and conventional neonatal BALB/c mice. I. Preferential utilization of the CH-proximal VH gene family PC7183. Eur J Immunol 19:1811–1815

    Article  PubMed  CAS  Google Scholar 

  33. Eisen HN, Siskind GW (1964) Variations in affinities of antibodies during the immune response. Biochemistry 3:996–1008

    Article  PubMed  CAS  Google Scholar 

  34. Gupta SC, Hengartner H, Zinkernagel RM (1986) Primary antibody responses to a well-defined and unique hapten are not enhanced by preimmunization with carrier: analysis in a viral model. Proc Natl Acad Sci USA 83:2604–2608

    Article  PubMed  CAS  Google Scholar 

  35. Roost HP, Bachmann MF, Haag A, Kalinke U, Pliska V, Hengartner H, Zinkernagel RM (1995) Early high-affinity neutralizing anti-viral IgG responses without further overall improvements of affinity. Proc Natl Acad Sci USA 92:1257–1261

    Article  PubMed  CAS  Google Scholar 

  36. Bachmann MF, Kalinke U, Althage A, Freer G, Burkhart C, Roost H, Aguet M, Hengartner H, Zinkernagel RM (1997) The role of antibody concentration and avidity in antiviral protection. Science 276:2024–2027

    Article  PubMed  CAS  Google Scholar 

  37. Seiler P, Senn BM, Klenerman P, Kalinke U, Hengartner H, Zinkernagel RM (2000) Additive effect of neutralizing antibody and antiviral drug treatment in preventing virus escape and persistence. J Virol 74:5896–5901

    Article  PubMed  CAS  Google Scholar 

  38. Hangartner L, Senn BM, Ledermann B, Kalinke U, Seiler P, Bucher E, Zellweger RM, Fink K, Odermatt B, Burki K, Zinkernagel RM, Hengartner H (2003) Antiviral immune responses in gene-targeted mice expressing the immunoglobulin heavy chain of virus-neutralizing antibodies. Proc Natl Acad Sci USA 100:12883–12888

    Article  PubMed  CAS  Google Scholar 

  39. Hangartner L, Zinkernagel RM, Hengartner H (2006) Antiviral antibody responses: the two extremes of a wide spectrum. Nat Rev Immunol 6:231–243

    Article  PubMed  CAS  Google Scholar 

  40. Griffiths GM, Berek C, Kaartinen M, Milstein C (1984) Somatic mutation and the maturation of immune response to 2-phenyl oxazolone. Nature 312:271–275

    Article  PubMed  CAS  Google Scholar 

  41. Weiss U, Zoebelein R, Rajewsky K (1992) Accumulation of somatic mutants in the B cell compartment after primary immunization with a T cell-dependent antigen. Eur J Immunol 22:511–517

    Article  PubMed  CAS  Google Scholar 

  42. Stiegler G, Kunert R, Purtscher M, Wolbank S, Voglauer R, Steindl F, Katinger H (2001) A potent cross-clade neutralizing human monoclonal antibody against a novel epitope on gp41 of human immunodeficiency virus type 1. AIDS Res Hum Retroviruses 17:1757–1765

    Article  PubMed  CAS  Google Scholar 

  43. Kimata JT, Kuller L, Anderson DB, Dailey P, Overbaugh J (1999) Emerging cytopathic and antigenic simian immunodeficiency virus variants influence AIDS progression. Nat Med 5:535–541

    Article  PubMed  CAS  Google Scholar 

  44. Mitchison NA (1971) The carrier effect in the secondary response to hapten-protein conjugates. V. Use of antilymphocyte serum to deplete animals of helper cells. Eur J Immunol 1:68–75

    Article  PubMed  CAS  Google Scholar 

  45. Rajewsky K, Schirrmacher V, Nase S, Jerne NK (1969) The requirement of more than one antigenic determinant for immunogenicity. J Exp Med 129:1131–1143

    Article  PubMed  CAS  Google Scholar 

  46. Bachmann MF, Kundig TM, Kalberer CP, Hengartner H, Zinkernagel RM (1994) How many specific B cells are needed to protect against a virus? J Immunol 152:4235–4241

    PubMed  CAS  Google Scholar 

  47. Nathanson N, Martin JR (1979) The epidemiology of poliomyelitis: enigmas surrounding its appearance, epidemicity, and disappearance. Am J Epidemiol 110:672–692

    PubMed  CAS  Google Scholar 

  48. Doherty PC, Kelso A (2008) Toward a broadly protective influenza vaccine. J Clin Invest 118:3273–3275

    PubMed  CAS  Google Scholar 

  49. Song JM, Van Rooijen N, Bozja J, Compans RW, Kang SM (2011) Vaccination inducing broad and improved cross protection against multiple subtypes of influenza A virus. Proc Natl Acad Sci USA 108:757–761

    Article  PubMed  CAS  Google Scholar 

  50. Wang TT, Tan GS, Hai R, Pica N, Ngai L, Ekiert DC, Wilson IA, Garcia-Sastre A, Moran TM, Palese P (2010) Vaccination with a synthetic peptide from the influenza virus hemagglutinin provides protection against distinct viral subtypes. Proc Natl Acad Sci USA 107:18979–18984

    Article  PubMed  CAS  Google Scholar 

  51. Walker LM, Simek MD, Priddy F, Gach JS, Wagner D, Zwick MB, Phogat SK, Poignard P, Burton DR (2010) A limited number of antibody specificities mediate broad and potent serum neutralization in selected HIV-1 infected individuals. PLoS Pathog 6:e1001028

    Article  PubMed  Google Scholar 

  52. Burton DR (2010) Scaffolding to build a rational vaccine design strategy. Proc Natl Acad Sci USA 107:17859–17860

    Article  PubMed  CAS  Google Scholar 

  53. Fauci AS, Johnston MI, Dieffenbach CW, Burton DR, Hammer SM, Hoxie JA, Martin M, Overbaugh J, Watkins DI, Mahmoud A, Greene WC (2008) HIV vaccine research: the way forward. Science 321:530–532

    Article  PubMed  CAS  Google Scholar 

  54. Halstead SB (1989) Antibody, macrophages, dengue virus infection, shock, and hemorrhage: a pathogenetic cascade. Rev Infect Dis 11(Suppl 4):S830–S839

    Article  PubMed  Google Scholar 

  55. Slifka MK, Antia R, Whitmire JK, Ahmed R (1998) Humoral immunity due to long-lived plasma cells. Immunity 8:363–372

    Article  PubMed  CAS  Google Scholar 

  56. Manz RA, Thiel A, Radbruch A (1997) Lifetime of plasma cells in the bone marrow. Nature 388:133–134

    Article  PubMed  CAS  Google Scholar 

  57. Planz O, Ehl S, Furrer E, Horvath E, Brundler MA, Hengartner H, Zinkernagel RM (1997) A critical role for neutralizing-antibody-producing B cells, CD4(+) T cells, and interferons in persistent and acute infections of mice with lymphocytic choriomeningitis virus: implications for adoptive immunotherapy of virus carriers. Proc Natl Acad Sci USA 94:6874–6879

    Article  PubMed  CAS  Google Scholar 

  58. Borst P, Bitter W, McCulloch R, Van Leeuwen F, Rudenko G (1995) Antigenic variation in malaria. Cell 82:1–4

    Article  PubMed  CAS  Google Scholar 

  59. Hunziker L, Recher M, Macpherson AJ, Ciurea A, Freigang S, Hengartner H, Zinkernagel RM (2003) Hypergammaglobulinemia and autoantibody induction mechanisms in viral infections. Nat Immunol 4:343–349

    Article  PubMed  CAS  Google Scholar 

  60. Bachmann MF, Kundig TM, Hengartner H, Zinkernagel RM (1994) Regulation of IgG antibody titers by the amount persisting of immune-complexed antigen. Eur J Immunol 24:2567–2570

    Article  PubMed  CAS  Google Scholar 

  61. Griffin DE (2010) Measles virus-induced suppression of immune responses. Immunol Rev 236:176–189

    Article  PubMed  CAS  Google Scholar 

  62. Riddell MA, Moss WJ, Hauer D, Monze M, Griffin DE (2007) Slow clearance of measles virus RNA after acute infection. J Clin Virol 39:312–317

    Article  PubMed  CAS  Google Scholar 

  63. Cattaneo R, Schmid A, Rebmann G, Baczko K, Ter Meulen V, Bellini WJ, Rozenblatt S, Billeter MA (1986) Accumulated measles virus mutations in a case of subacute sclerosing panencephalitis: interrupted matrix protein reading frame and transcription alteration. Virology 154:97–107

    Article  PubMed  CAS  Google Scholar 

  64. Katayama Y, Hotta H, Nishimura A, Tatsuno Y, Homma M (1995) Detection of measles virus nucleoprotein mRNA in autopsied brain tissues. J Gen Virol 76(Pt 12):3201–3204

    Article  PubMed  CAS  Google Scholar 

  65. Klenerman P, Hengartner H, Zinkernagel RM (1997) A non-retroviral RNA virus persists in DNA form. Nature 390:298–301

    Article  PubMed  CAS  Google Scholar 

  66. Geuking MB, Weber J, Dewannieux M, Gorelik E, Heidmann T, Hengartner H, Zinkernagel RM, Hangartner L (2009) Recombination of retrotransposon and exogenous RNA virus results in nonretroviral cDNA integration. Science 323:393–396

    Article  PubMed  CAS  Google Scholar 

  67. Rohani P, Zhong X, King AA (2010) Contact network structure explains the changing epidemiology of pertussis. Science 330:982–985

    Article  PubMed  CAS  Google Scholar 

  68. Bullens D, Smets K, Vanhaesebrouck P (2000) Congenital rubella syndrome after maternal reinfection. Clin Pediatr (Phila) 39:113–116

    Article  CAS  Google Scholar 

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    Rolf M. Zinkernagel

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Zinkernagel, R.M. Immunological memory ≠ protective immunity. Cell. Mol. Life Sci. 69, 1635–1640 (2012). https://doi.org/10.1007/s00018-012-0972-y

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