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  • Review Article
  • Published:

No one is naive: the significance of heterologous T-cell immunity

Key Points

  • CD8+ T-cell memory to viruses is stable, but memory is lost after infections with other viruses.

  • The homeostasis of CD8+ T-cell memory differs from that of CD4+ T-cell memory.

  • Crossreactive T-cell responses between heterologous viruses might be a common event.

  • The immunodominance of epitopes that are recognized by T cells is, in part, a function of a T-cell repertoire that is moulded by the past history of infection.

  • Viruses might cause the activation of memory T cells that are specific for previously encountered pathogens.

  • Memory T cells that are specific for unrelated pathogens might have roles in protective immunity and immunopathology caused by heterologous infectious agents.

  • Immune deviation, or the balance between T helper 1 (TH1) and TH2 responses, might be influenced by the memory T-cell pool that is specific for previously encountered pathogens.

Abstract

Memory T cells that are specific for one virus can become activated during infection with an unrelated heterologous virus, and might have roles in protective immunity and immunopathology. The course of each infection is influenced by the T-cell memory pool that has been laid down by a host's history of previous infections, and with each successive infection, T-cell memory to previously encountered agents is modified. Here, we discuss evidence from studies in mice and humans that shows the importance of this phenomenon in determining the outcome of infection.

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Figure 1: Potential mechanisms of T-cell crossreactivity.
Figure 2: Modulation of the T-cell repertoire during viral infection.
Figure 3: Protective heterologous immunity between viruses.
Figure 4: Model of heterologous immunity in the lung.
Figure 5: Comparison of pathology in fat and lung in models of heterologous immunity in mice, and in human diseases of unknown aetiology.

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References

  1. Matthew, A. et al. Predominance of HLA-restricted cytotoxic T-lymphocyte responses to serotype-cross-reactive epitopes on nonstructural proteins following natural secondary dengue virus infection. J. Virol. 72, 3999–4004 (1998).This study shows that different dengue-virus serotypes have high homology in terms of T-cell epitopes, and they induce crossreactive T-cell responses.

    Google Scholar 

  2. Halstead, S. B. Antibody, macrophages, dengue-virus infection, shock and hemorrhage: a pathogenetic cascade. Rev. Infect. Dis. 11, S830–S839 (1989).

    PubMed  Google Scholar 

  3. Bjorkman, P. J. MHC restriction in three dimensions: a view of T-cell receptor/ligand interactions. Cell 89, 167–170 (1997).

    CAS  PubMed  Google Scholar 

  4. Yewdell, J. W. & Bennink, J. R. Immunodominance in major histocompatibility complex class-I-restricted T-lymphocyte responses. Annu. Rev. Immunol. 17, 51–88 (1999).

    CAS  PubMed  Google Scholar 

  5. Falk, K., Rotzschke, O., Stevanovic, S., Jung, G. & Rammensee, H. Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature 351, 290–296 (1991).

    CAS  PubMed  Google Scholar 

  6. Kaech, S. M. & Ahmed, R. Memory CD8+ T-cell differentiation: initial antigen encounter triggers a developmental program in naive cells. Nature Immunol. 2, 415–422 (2001).

    CAS  Google Scholar 

  7. van Stipdonk, M. J., Lemmens, E. E. & Schoenberger, S. P. Naive CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation. Nature Immunol. 2, 423–429 (2001).

    CAS  Google Scholar 

  8. Mercado, R. et al. Early programming of T-cell populations responding to bacterial infection. J. Immunol. 165, 6833–6839 (2000).

    CAS  PubMed  Google Scholar 

  9. Selin, L. K., Vergilis, K., Welsh, R. M. & Nahill, S. R. Reduction of otherwise remarkably stable virus-specific cytotoxic T-lymphocyte memory by heterologous viral infections. J. Exp. Med. 183, 2489–2499 (1996).This study quantifies the expanding number of virus-specific CD8+ T cells during viral infections, and shows that this population remains stable in long-term memory, and that heterologous virus infections disrupt this stability and cause reductions in the memory response to previously encountered viruses.

    CAS  PubMed  Google Scholar 

  10. Razvi, E. S., Jiang, Z., Woda, B. A. & Welsh, R. M. Lymphocyte apoptosis during the silencing of the immune response to acute viral infections in normal, lpr and Bcl-2-transgenic mice. Am. J. Pathol. 147, 79–91 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Masopust, D., Vezys, V., Marzo, A. L. & Lefrancois, L. Preferential localization of effector memory cells in nonlymphoid tissue. Science 291, 2413–2417 (2001).Memory T cells reside at high frequencies in peripheral organs.

    CAS  PubMed  Google Scholar 

  12. Marshall, D. R. et al. Measuring the diaspora for virus-specific CD8+ T cells. Proc. Natl Acad. Sci. USA 98, 6313–6318 (2001).This report describes how memory CD8+ T cells migrate into peripheral organs as they disappear from the lymphoid organs at the end stage of the T-cell response to viral infections.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Van der Most, R. G. et al. Identification of Db- and Kb-restricted subdominant cytotoxic T-cell responses in lymphocytic choriomeningitis virus-infected mice. Virology 240, 158–167 (1998).

    CAS  PubMed  Google Scholar 

  14. Chen, W., Anton, L. C., Bennink, J. R. & Yewdell, J. W. Dissecting the multifactorial causes of immunodominance in class-I-restricted T-cell responses to viruses. Immunity 12, 83–93 (2000).

    CAS  PubMed  Google Scholar 

  15. Vitiello, A. et al. Immunodominance analysis of CTL responses to influenza PR8 virus reveals two dominant and subdominant Kb-restricted epitopes. J. Immunol. 157, 5555–5562 (1996).

    CAS  PubMed  Google Scholar 

  16. Stevenson, P. G., Belz, G. T., Altman, J. D. & Doherty, P. C. Changing patterns of dominance in the CD8+ T-cell response during acute and persistent murine γ-herpesvirus infection. Eur. J. Immunol. 29, 1059–1067 (1999).

    CAS  PubMed  Google Scholar 

  17. Wallace, M. E., Keating, R., Heath, W. R. & Carbone, F. R. The cytotoxic T-cell response to herpes simplex virus type 1 infection of C57BL/6 mice is almost entirely directed against a single immunodominant determinant. J. Virol. 73, 7619–7626 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Belz, G. T., Stevenson, P. G. & Doherty, P. C. Contemporary analysis of MHC-related immunodominance hierarchies in the CD8+ T-cell response to influenza A viruses. J. Immunol. 165, 2404–2409 (2000).

    CAS  PubMed  Google Scholar 

  19. Lin, M. Y. & Welsh, R. M. Stability and diversity of T-cell receptor (TCR) repertoire usage during lymphocytic choriomeningitis virus infection of mice. J. Exp. Med. 188, 1993–2005 (1998).The virus-induced T-cell repertoire usage differs between genetically identical mice, even though the specificity of the CD8+ T-cell response is similar.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Bousso, P. et al. Individual variations in the murine T-cell response to a specific peptide reflect variability in naive repertoire. Immunity 9, 169–178 (1998).

    CAS  PubMed  Google Scholar 

  21. Blattman, J. N., Sourdive, D. J., Murali-Krishna, K., Ahmed, R. & Altman, J. D. Evolution of the T-cell repertoire during primary, memory and recall responses to viral infection. J. Immunol. 165, 6081–6090 (2000).

    CAS  PubMed  Google Scholar 

  22. Mason, D. A very high level of crossreactivity is an essential feature of the T-cell repertoire. Immunol. Today 19, 395–404 (1998).This paper provides theoretical calculations that indicate that T cells must be highly crossreactive.

    CAS  PubMed  Google Scholar 

  23. Tabi, Z., Lynch, F., Ceredig, R., Allan, J. E. & Doherty, P. C. Virus-specific memory T cells are Pgp-1+ and can be selectively activated with phorbol ester and calcium ionophore. Cell. Immunol. 113, 268–277 (1988).

    CAS  PubMed  Google Scholar 

  24. Bradley, L. M., Croft, M. & Swain, S. L. T-cell memory: new perspectives. Immunol. Today 14, 197–199 (1993).

    CAS  PubMed  Google Scholar 

  25. Pihlgren, M., Dubois, P. M., Tomkowiak, M., Sjogren, T. & Marvel, J. Resting memory CD8+ T cells are hyperactive to antigenic challenge in vitro. J. Exp. Med. 184, 2141–2151 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Curtsinger, J. M., Lins, D. C. & Mescher, M. F. CD8+ memory T cells (CD44high, Ly-6C+) are more sensitive than naive cells (CD44low, Ly6C) to TCR/CD8 signaling in response to antigen. J. Immunol. 160, 3236–3243 (1998).

    CAS  PubMed  Google Scholar 

  27. Veiga-Fernandes, H., Walter, U., Bourgeois, C., McLean, A. & Rocha, B. Response of naive and memory CD8 T cells to antigen stimulation in vivo. Nature Immunol. 1, 47–53 (2000).

    CAS  Google Scholar 

  28. Sheil, J. M., Bevan, M. J. & Lefrancois, L. Characterization of dual-reactive H-2Kb-restricted anti-vesicular stomatitis virus and alloreactive cytotoxic T cells. J. Immunol. 138, 3654–3660 (1987).

    CAS  PubMed  Google Scholar 

  29. Braciale, T. J., Andrew, M. E. & Braciale, V. L. Simultaneous expression of H-2-restricted and alloreactive recognition by a cloned line of influenza virus-specific cytotoxic T lymphocytes. J. Exp. Med. 153, 1371–1376 (1981).

    CAS  PubMed  Google Scholar 

  30. Anderson, R. W., Bennick, J. R., Yewdell, J. W., Maloy, W. L. & Coligan, J. E. Influenza basic polymerase 2 peptides are recognized by influenza nucleoprotein-specific cytotoxic T lymphocytes. Mol. Immunol. 29, 1089–1096 (1992).

    CAS  PubMed  Google Scholar 

  31. Kuwano, K., Reyes, R. E., Humphreys, R. E. & Ennis, F. A. Recognition of disparate HA and NS1 peptides by an H-2kd-restricted, influenza-specific CTL clone. Mol. Immunol. 28, 1–7 (1991).

    CAS  PubMed  Google Scholar 

  32. Yang, H. & Welsh, R. M. Induction of alloreactive cytotoxic T cells by acute virus infection of mice. J. Immunol. 136, 1186–1193 (1986).

    CAS  PubMed  Google Scholar 

  33. Tomkinson, B. E., Maziarz, R. & Sullivan, J. L. Characterization of the T-cell-mediated cellular cytotoxicity during infectious mononucleosis. J. Immunol. 143, 660–670 (1989).

    CAS  PubMed  Google Scholar 

  34. Strang, G. & Rickinson, A. B. Multiple HLA class-I-dependent cytotoxicities constitute the 'non-HLA-restricted' response in infectious mononucleosis. Eur. J. Immunol. 17, 1007–1013 (1987).

    CAS  PubMed  Google Scholar 

  35. Burrows, S. R. et al. Cross-reactive memory T cells for Epstein–Barr virus augment the alloresponse to common human leukocyte antigens: degenerate recognition of major histocompatibility complex-bound peptide by T cells and its role in alloreactivity. Eur. J. Immunol. 27, 1726–1736 (1997).

    CAS  PubMed  Google Scholar 

  36. Burrows, S. R., Khanna, R., Silins, S. L. & Moss, D. J. The influence of antiviral T-cell responses on the alloreactive repertoire. Immunol. Today 20, 203–207 (1999).

    CAS  PubMed  Google Scholar 

  37. Nahill, S. R. & Welsh, R. M. High frequency of cross-reactive cytotoxic T lymphocytes elicited during the virus-induced polyclonal cytotoxic T-lymphocyte response. J. Exp. Med. 177, 317–327 (1993).

    CAS  PubMed  Google Scholar 

  38. Selin, L. K., Nahill, S. R. & Welsh, R. M. Cross-reactivities in memory cytotoxic T-lymphocyte recognition of heterologous viruses. J. Exp. Med. 179, 1933–1943 (1994).

    CAS  PubMed  Google Scholar 

  39. Yang, H., Dundon, P. L., Nahill, S. R. & Welsh, R. M. Virus-induced polyclonal cytotoxic T-lymphocyte stimulation. J. Immunol. 142, 1710–1718 (1989).

    CAS  PubMed  Google Scholar 

  40. Daniel, C., Horvath, S. & Allen, P. M. A basis for alloreactivity: MHC helical residues broaden peptide recognition by the TCR. Immunity 8, 543–552 (1998).

    CAS  PubMed  Google Scholar 

  41. Speir, J. A. et al. Structural basis of 2C TCR allorecognition of H-2Ld peptide complexes. Immunity 8, 553–562 (1998).

    CAS  PubMed  Google Scholar 

  42. Alam, S. M. & Gascoigne, N. R. Posttranslational regulation of TCR Vα allelic exclusion during T-cell differentiation. J. Immunol. 160, 3883–3890 (1998).

    CAS  PubMed  Google Scholar 

  43. Welsh, R. M. et al. Virus-induced abrogation of transplantation tolerance induced by donor-specific transfusion and anti-CD154 antibody. J. Virol. 74, 2210–2218 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Betts, M. R. et al. Putative immunodominant human immunodeficiency virus-specific CD8+ T-cell responses cannot be predicted by major histocompatibility complex class I haplotype. J. Virol. 74, 9144–9151 (2000).These authors show that predictable hierarchies of immunodominant epitopes of HIV are not seen in the 'wild' human population.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Day, C. L. et al. Relative dominance of epitope-specific cytotoxic T-lymphocyte responses in human immunodeficiency virus type-1-infected persons with shared HLA alleles. J. Virol. 75, 6279–6291 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Fazekas de St Groth, S. & Webster, R. G. Disquisitions on original antigenic sin. II. Proof in lower creatures. J. Exp. Med. 124, 347–361 (1966).

    CAS  PubMed  Google Scholar 

  47. Haanan, J. B., Wolkers, M. C., Kruisbeek, A. M. & Schumacher, T. N. Selective expansion of cross-reactive CD8+ memory T cells by viral variants. J. Exp. Med. 190, 1319–1328 (1999).This study used viral strain-specific tetramers to show that a related virus will selectively stimulate the expansion of crossreactive but not non-crossreactive CD8+ T-cell populations during infection.

    Google Scholar 

  48. Klenerman, P. & Zinkernagel, R. M. Original antigenic sin impairs cytotoxic T-lymphocyte responses to viruses bearing variant epitopes. Nature 394, 421–422 (1998).

    Google Scholar 

  49. Tough, D. F., Borrow, P. & Sprent, J. Induction of bystander T-cell proliferation by viruses and type I interferon in vivo. Science 272, 1947–1950 (1996).

    CAS  PubMed  Google Scholar 

  50. Sprent, J., Zhang, X., Sun, S. & Tough, D. T-cell turnover in vivo and the role of cytokines. Immunol. Lett. 65, 21–25 (1999).

    CAS  PubMed  Google Scholar 

  51. Zarozinski, C. C. & Welsh, R. M. Minimal bystander activation of CD8 T cells during the virus-induced polyclonal T-cell response. J. Exp. Med. 185, 1629–1639 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. McNally, J. M. et al. Attrition of bystander CD8 T cells during virus-induced T-cell and interferon responses. J. Virol. 75, 5965–5976 (2001).This report shows that non-virus-specific 'bystander' CD8+ T cells are reduced in number during virus infections and that type I IFN induces the apoptosis of memory CD8+ T cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Mahalingam, S., Foster, P. S., Lobigs, S., Farber, J. M. & Karupiah, G. Interferon-inducible chemokines and immunity to poxvirus infections. Immunol. Rev. 177, 127–133 (2000).

    CAS  PubMed  Google Scholar 

  54. Topham, D. J., Castrucci, M., Wingo, F. S., Belz, G. T. & Doherty, P. C. The role of antigen in the localization of naive, acutely activated and memory CD8+ T cells to the lung during influenza pneumonia. J. Immunol. 167, 6983–6990 (2001).

    CAS  PubMed  Google Scholar 

  55. Ku, C. C., Murakami, M., Sakamoto, A., Kappler, J. & Marrack, P. Control of homeostasis of CD8+ memory T cells by opposing cytokines. Science 288, 675–678 (2000).

    CAS  PubMed  Google Scholar 

  56. Flynn, K. J., Riberdy, J. M., Christensen, J. P., Altman, J. D. & Doherty, P. C. In vivo proliferation of naive and memory influenza-specific CD8+ T cells. Proc. Natl Acad. Sci. USA 96, 8597–8602 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Belz, G. T. & Doherty, P. C. Virus-specific and bystander CD8+ T-cell proliferation in the persistent phases of a γ-herpesvirus infection. J. Virol. 75, 4435–4438 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Turner, S. J., Cross, R., Xie, W. & Doherty, P. C. Concurrent naive and memory CD8+ T-cell responses to an influenza virus. J. Immunol. 167, 2753–2758 (2001).

    CAS  PubMed  Google Scholar 

  59. Lau, L. L., Jamieson, B. D., Somasundaram, T. & Ahmed, R. Cytotoxic T-cell memory without antigen. Nature 369, 648–652 (1994).

    CAS  PubMed  Google Scholar 

  60. Homann, D., Teyton, L. & Oldstone, M. B. Differential regulation of antiviral T-cell immunity results in stable CD8+ but declining CD4+ memory. Nature Med. 7, 892–893 (2001).

    Google Scholar 

  61. Razvi, E. S., Welsh, R. M. & McFarland, H. I. In vivo state of antiviral CTL precursors: characterization of a cycling population containing CTL precursors in immune mice. J. Immunol. 154, 620–632 (1995).

    CAS  PubMed  Google Scholar 

  62. Sprent, J. & Tough, D. F. Lymphocyte life-span and memory. Science 265, 1395–1400 (1994).

    CAS  PubMed  Google Scholar 

  63. Zimmermann, C., Brduscha-Riem, K., Blaser, C., Zinkernagel, R. M. & Pircher, H. Visualization, characterization and turnover of CD8+ memory T cells in virus-infected hosts. J. Exp. Med. 183, 1367–1375 (1996).

    CAS  Google Scholar 

  64. Selin, L. K. et al. Attrition of T-cell memory: selective loss of lymphocytic choriomeningitis virus (LCMV) epitope-specific memory CD8 T cells following infections with heterologous viruses. Immunity 11, 733–742 (1999).This study shows that CD8+ T cells that are specific for previously encountered viruses are reduced in number by heterologous viral infections, and there is a selective loss of some specificities but not others.

    CAS  PubMed  Google Scholar 

  65. Chen, H. D. et al. Memory CD8+ T cells in heterologous antiviral immunity and immunopathology in the lung. Nature Immunol. 2, 1067–1076 (2001).This study shows the recruitment and activation of LCMV-specific memory T cells into the lung during vaccinia virus infection, which results in marked immunopathology in a respiratory model of heterologous immunity.

    CAS  Google Scholar 

  66. Varga, S. M. & Welsh, R. M. Cutting edge: detection of a high frequency of virus-specific CD4+ T cells during acute infection with lymphocytic choriomeningitis virus. J. Immunol. 161, 3215–3218 (1998).

    CAS  PubMed  Google Scholar 

  67. Varga, S. M. & Welsh, R. M. High frequency of virus-specific interleukin-2-producing CD4+ T cells and TH1 dominance during lymphocytic choriomeningitis virus infection. J. Virol. 74, 4429–4432 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Varga, S. M., Selin, L. K. & Welsh, R. M. Independent regulation of lymphocytic choriomeningitis virus-specific T-cell memory pools: relative stability of CD4 memory under conditions of CD8 memory T-cell loss. J. Immunol. 166, 1554–1561 (2001).This study shows that heterologous viral infections cause less of a decline in CD4+ T-cell memory than they do in CD8+ T-cell memory.

    CAS  PubMed  Google Scholar 

  69. Selin, L. K., Varga, S. M., Wong, I. C. & Welsh, R. M. Protective heterologous antiviral immunity and enhanced immunopathogenesis mediated by memory T-cell populations. J. Exp. Med. 188, 1705–1715 (1998).This shows the principle of heterologous immunity and immunopathology during viral infections.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Schlesinger, C., Meyer, C. A., Veeraraghavan, S. & Koss, M. N. Constrictive (obliterative) bronchiolitis: diagnosis, etiology and a critical review of the literature. Ann. Diagn. Pathol. 2, 321–334 (1998).

    CAS  PubMed  Google Scholar 

  71. Ploegh, H. L. Viral strategies of immune evasion. Science 280, 248–253 (1998).

    CAS  PubMed  Google Scholar 

  72. Aaby, P. et al. Non-specific beneficial effect of measles immunisation: analysis of mortality studies from developing countries. BMJ 311, 481–485 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Doherty, P. C. et al. Effector CD4+ and CD8+ T-cell mechanisms in the control of respiratory virus infections. Immunol. Rev. 159, 105–117 (1997).

    CAS  PubMed  Google Scholar 

  74. Jameson, J., Cruz, J. & Ennis, F. A. Human cytotoxic T-lymphocyte repertoire to influenza A viruses. J. Virol. 72, 8682–8689 (1998).This paper identifies several influenza virus T-cell epitopes, some of which are crossreactive between strains.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Yang, H., Joris, I., Majno, G. & Welsh, R. M. Necrosis of adipose tissue induced by sequential infections with unrelated viruses. Am. J. Pathol. 120, 173–177 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Bolognia, J. & Braverman, I. M. In Harrison's Principles of Internal Medicine (eds Isselbacher, K. J. et al.) 290–307 (McGraw–Hill, New York, 1992).

    Google Scholar 

  77. Zhao, Z.-S., Granucci, F., Yeh, L., Schaffer, P. A. & Cantor, H. Molecular mimicry by herpes simplex virus type-1: autoimmune disease after viral infection. Science 279, 1344–1347 (1998).

    CAS  PubMed  Google Scholar 

  78. Evans, C. F., Horwitz, M. S., Hobbs, M. V. & Oldstone, M. B. Viral infection of transgenic mice expressing a viral protein in oligodendrocytes leads to chronic central nervous system autoimmune disease. J. Exp. Med. 184, 2371–2384 (1996).This study shows that a virus can break tolerance to a transgene in the brain and induce transient encephalitis, which will undergo remission until exacerbated by a heterologous virus infection.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Swain, S. L. Helper T-cell differentiation. Curr. Opin. Immunol. 11, 180–185 (1999).

    CAS  PubMed  Google Scholar 

  80. Ismail, N. & Bretscher, P. A. More antigen-dependent CD4+ T cell/CD4+ T cell interactions are required for the primary generation of TH2 than of TH1 cells. Eur. J. Immunol. 31, 1765–1771 (2001).

    CAS  PubMed  Google Scholar 

  81. Swain, S. L. Interleukin-18: tipping the balance towards a T helper cell 1 response. J. Exp. Med. 194, F11–F14 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Cohn, L., Herrick, C., Niu, N., Homer, R. & Bottomly, K. IL-4 promotes airways eosinophilia by suppressing IFN-γ production: defining a novel role for IFN-γ in the regulation of allergic airway inflammation. J. Immunol. 166, 2760–2767 (2001).

    CAS  PubMed  Google Scholar 

  83. Rook, G. A. & Stanford, J. L. Give us this day our daily germs. Immunol. Today 19, 113–116 (1998).

    CAS  PubMed  Google Scholar 

  84. Varga, S. M., Wang, X., Welsh, R. M. & Braciale, T. J. Immunopathology in RSV infection is mediated by a discrete oligoclonal subset of antigen-specific CD4+ T cells. Immunity 15, 637–646 (2001).

    CAS  PubMed  Google Scholar 

  85. Kapikian, A. Z., Mitchell, R. H., Chanock, R. M., Shvedoff, R. A. & Stewart, C. E. An epidemiological study of altered clinical reactivity to respiratory syncytial (RS) virus infection in children previously vaccinated with an inactivated RS virus vaccine. Am. J. Epidemiol. 89, 405–421 (1969).

    CAS  PubMed  Google Scholar 

  86. Cohn, L., Homer, R. J., Niu, N. & Bottomly, K. T helper 1 cells and interferon-γ regulate allergic airway inflammation and mucus production. J. Exp. Med. 190, 1309–1318 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Graham, B. S., Bunton, L. A., Wright, P. F. & Karzon, D. T. Role of T-lymphocyte subsets in the pathogenesis of primary infection and rechallenge with respiratory syncytial virus in mice. J. Clin. Invest. 88, 1026–1033 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Walzl, G., Tafuro, S., Moss, P., Openshaw, P. J. & Hussell, T. Influenza virus lung infection protects from respiratory syncytial virus-induced immunopathology. J. Exp. Med. 192, 1317–1326 (2000).A heterologous influenza-virus infection can alter the ability of a vaccinia-virus recombinant to prime a host to make a damaging T H 2-like response to RSV.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Johnson, T. R. & Graham, B. S. Secreted respiratory syncytial virus G glycoprotein induces interleukin-5 (IL-5), IL-13 and eosinophilia by an IL-4-dependent mechanism. J. Virol. 73, 8485–8495 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Shirakawa, T., Enomoto, T., Shimazu, S. & Hopkin, J. M. The inverse association between tuberculin responses and atopic disorder. Science 275, 77–79 (1997).

    CAS  PubMed  Google Scholar 

  91. Martinez, F. D. et al. Asthma and wheezing in the first six years of life. N. Engl. J. Med. 332, 133–138 (1995).

    CAS  PubMed  Google Scholar 

  92. Shaheen, S. O. et al. Measles and atopy in Guinea–Bissau. Lancet 347, 1792–1796 (1996).

    CAS  PubMed  Google Scholar 

  93. Erb, K. J., Holloway, J. W., Sobeck, A., Moll, H. & Le Gros, G. Infection of mice with Mycobacterium bovis bacillus Calmette–Guerin (BCG) suppresses allergen-induced airway eosinophilia. J. Exp. Med. 187, 561–569 (1998).This study shows that a history of BCG infection can render a host refractory to the induction of a T H 2 response by an allergen.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Wedemeyer, H., Mizukoshi, E., Davis, A. R., Bennink, J. R. & Rehermann, B. Cross-reactivity between hepatitis C virus and influenza A virus determinant-specific cytotoxic T cells. J. Virol. 75, 11392–11400 (2001).Defines a strong crossreactive epitope between hepatitis C virus and influenza virus.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Weinstein, L. & Meade, R. H. Respiratory manifestations of chickenpox. Arch. Intern. Med. 98, 91–99 (1956).

    CAS  Google Scholar 

  96. Rickinson, A. B. & Kieff, E. In Virology Vol. 2 (eds Fields, B. N. et al.) 2397–2446 (Lippincott–Raven, Philadelphia, 1996).

    Google Scholar 

  97. Moss, D. J., Burrows, S. R., Silins, S. L., Misko, I. & Khanna, R. The immunology of Epstein–Barr virus infection. Philos Trans R Soc Lond B Biol Sci 356, 475–488 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Kaul, R. et al. CD8+ lymphocytes respond to different HIV epitopes in seronegative and infected subjects. J. Clin. Invest. 107, 1303–1310 (2001).This study provides evidence of HIV-specific T cells in seronegative and HIV-negative subjects at high risk of HIV infection.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Tillmann, H. L. et al. Infection with GB virus C and reduced mortality among HIV-infected patients. N. Engl. J. Med. 345, 715–724 (2001).

    CAS  PubMed  Google Scholar 

  100. Xiang, J. et al. Effect of coinfection with GB virus C on survival among patients with HIV infection. N. Engl. J. Med. 345, 707–714 (2001).

    CAS  PubMed  Google Scholar 

  101. Barnett, L. A. & Fujinami, R. S. Molecular mimicry: a mechanism for autoimmune injury. FASEB J. 6, 840–844 (1992).

    CAS  PubMed  Google Scholar 

  102. Janeway, C. A. Innate immunity acknowledged. Immunologist 3, 198–200 (1995).

    CAS  Google Scholar 

  103. Smoller, B. R., Weishar, M. & Gray, M. H. An unusual cutaneous manifestation in Crohn's disease. Arch Pathol Lab Med 114, 609–610 (1990).

    CAS  PubMed  Google Scholar 

  104. Brehm, M. B. et al. T-cell immunodominance and maintenance of memory regulated by unexpectedly cross-reactive pathogens. Nature Immunol. (in the press). This study shows that cross-reactive CD8+ T-cell responses during heterologous virus infections influence immunodominance, as the T cells that are specific for the cross-reactive memory epitopes dominate acute responses to the second virus and are preferentially maintained in memory of the first virus, whereas non-crossreactive memory T cells are lost.

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Acknowledgements

R.M.W. and L.K.S. are supported by the United States National Institutes of Health. The contents of this article are solely the responsibility of the authors and do not represent the official views of the NIH. We thank M. Brehm, A. Fraire, I. Joris, B. Smoller and H. Chen for their collaborations and helpful comments.

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Correspondence to Liisa K. Selin.

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DATABASES

Entrez

dengue virus

Ebola virus

EBV

GBV-C flavivirus

hepatitis C virus

HIV-1

influenza virus

haemagglutinin gene

measles virus

mouse γ-herpesvirus

Mycobacterium tuberculosis

pertussis

RSV

vaccinia virus

varicella zoster virus

VSV

yellow-fever virus

LocusLink

CD44

HLA-A

IFN-γ (human)

IFN-γ (mouse)

IL-5

IL-15

LFA1

type I interferon

OMIM

multiple sclerosis

systemic lupus erythematosus

Glossary

T-HELPER TYPE 1/2

(TH1/TH2). At least two distinct subsets of activated CD4+ T cells have been described. TH1 cells produce IFN-γ, lymphotoxin and TNF, and support cell-mediated immunity. TH2 cells produce IL-4, IL-5 and IL-13, support humoral immunity, and downregulate TH1 responses.

CO-STIMULATION

Optimal signalling through the TCR complex requires accessory cell-surface molecules, such as CD28 or LFA1. Signals that are delivered from these molecules contribute to enhancing the immune response. In the absence of these co-stimulatory signals, naive T cells become unresponsive to a subsequent challenge with antigen.

CFSE

(5,6-carboxy-fluorescein diacetate succinimidyl ester). This a fluorescent dye that is used to label cells. With each cell division, the label is distributed equally into daughter cells. The loss of fluorescence intensity is used to calculate the number of cell divisions.

BYSTANDER ACTIVATION

The term, as it is used here, refers to the activation of T cells in which the TCRs are not being triggered by the antigens that are driving the immune response. This activation might be mediated by cytokines.

CLONAL IMPRINTING/ORIGINAL ANTIGENIC SIN

Previous exposure to one virus strain diverts the antibody response after exposure to a second virus strain to epitopes that are shared between the two strains.

BROMODEOXYURIDINE

(BrdU). A thymidine analogue that can be incorporated into DNA during S-phase when cells are exposed to this substance. Cells that have incorporated BrdU, and presumably have divided, can be visualized with anti-BrdU antibodies using flow cytometry.

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Welsh, R., Selin, L. No one is naive: the significance of heterologous T-cell immunity. Nat Rev Immunol 2, 417–426 (2002). https://doi.org/10.1038/nri820

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