1887

Abstract

Reconstitution of the virus-specific CD8 T-cell response is crucial for the prevention of human cytomegalovirus (CMV)-associated pathogenesis in transplant patients and human immunodeficiency virus-infected individuals. Although adoptive T-cell immunotherapy has been used successfully in various clinical settings, prophylactic vaccination remains the most amenable strategy to prevent CMV disease. However, vaccination in clinical settings where the host is severely immunocompromised due to the loss of CD4 T cells remains a significant challenge. This study investigated the efficacy of a chimeric CMV vaccine in a model setting that allowed studies on the generation of CD8 T-cell memory responses in a transient CD4 T-cell-deficient setting similar to that seen in immunocompromised patients. Immunization with an adenoviral CMV vaccine under transient helpless (complete CD4 T-cell depletion) or help-deficient (partial CD4 T-cell depletion) conditions demonstrated that induction of the effector CD8 T-cell and humoral responses was almost completely eliminated under helpless conditions, and was gradually regained with the recovery of CD4 T cells. However, this response failed to protect the host from viral infection, suggesting that lack of CD4 T cells during vaccination can significantly impair the priming and maturation of CMV-specific immune responses. Furthermore, although the induction of CMV-specific immune responses was also significantly reduced in a help-deficient environment, these primed effector cells could mature normally and generate long-term polyfunctional memory responses capable of restricting virus replication . These results highlight the importance of monitoring CD4 T-cell numbers before vaccination for the successful implementation of a CMV vaccine in an immunocompromised setting.

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2010-12-01
2019-11-20
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References

  1. Boyman, O., Kovar, M., Rubinstein, M. P., Surh, C. D. & Sprent, J. ( 2006; ). Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science 311, 1924–1927.[CrossRef]
    [Google Scholar]
  2. Darrah, P. A., Patel, D. T., De Luca, P. M., Lindsay, R. W., Davey, D. F., Flynn, B. J., Hoff, S. T., Andersen, P., Reed, S. G. & other authors ( 2007; ). Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major. Nat Med 13, 843–850.[CrossRef]
    [Google Scholar]
  3. Elkington, R., Walker, S., Crough, T., Menzies, M., Tellam, J., Bharadwaj, M. & Khanna, R. ( 2003; ). Ex vivo profiling of CD8+-T-cell responses to human cytomegalovirus reveals broad and multispecific reactivities in healthy virus carriers. J Virol 77, 5226–5240.[CrossRef]
    [Google Scholar]
  4. Firat, H., Tourdot, S., Ureta-Vidal, A., Scardino, A., Suhrbier, A., Buseyne, F., Riviere, Y., Danos, O., Michel, M. L. & other authors ( 2001; ). Design of a polyepitope construct for the induction of HLA-A0201-restricted HIV 1-specific CTL responses using HLA-A*0201 transgenic, H-2 class I KO mice. Eur J Immunol 31, 3064–3074.[CrossRef]
    [Google Scholar]
  5. Gandhi, M. K. & Khanna, R. ( 2004; ). Human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments. Lancet Infect Dis 4, 725–738.[CrossRef]
    [Google Scholar]
  6. Janssen, E. M., Lemmens, E. E., Wolfe, T., Christen, U., von Herrath, M. G. & Schoenberger, S. P. ( 2003; ). CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421, 852–856.[CrossRef]
    [Google Scholar]
  7. Janssen, E. M., Droin, N. M., Lemmens, E. E., Pinkoski, M. J., Bensinger, S. J., Ehst, B. D., Griffith, T. S., Green, D. R. & Schoenberger, S. P. ( 2005; ). CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death. Nature 434, 88–93.[CrossRef]
    [Google Scholar]
  8. Kaech, S. M., Tan, J. T., Wherry, E. J., Konieczny, B. T., Surh, C. D. & 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, 1191–1198.[CrossRef]
    [Google Scholar]
  9. Kieper, W. C., Tan, J. T., Bondi-Boyd, B., Gapin, L., Sprent, J., Ceredig, R. & Surh, C. D. ( 2002; ). Overexpression of interleukin (IL)-7 leads to IL-15-independent generation of memory phenotype CD8+ T cells. J Exp Med 195, 1533–1539.[CrossRef]
    [Google Scholar]
  10. McKay, P. F., Schmitz, J. E., Barouch, D. H., Kuroda, M. J., Lifton, M. A., Nickerson, C. E., Gorgone, D. A. & Letvin, N. L. ( 2002; ). Vaccine protection against functional CTL abnormalities in simian human immunodeficiency virus-infected rhesus monkeys. J Immunol 168, 332–337.[CrossRef]
    [Google Scholar]
  11. Pascolo, S., Bervas, N., Ure, J. M., Smith, A. G., Lemonnier, F. A. & Perarnau, B. ( 1997; ). HLA-A2.1-restricted education and cytolytic activity of CD8+ T lymphocytes from β2 microglobulin (β2m) HLA-A2.1 monochain transgenic H-2Db β2m double knockout mice. J Exp Med 185, 2043–2051.[CrossRef]
    [Google Scholar]
  12. Rapetti, L., Meunier, S., Pontoux, C. & Tanchot, C. ( 2008; ). CD4 help regulates expression of crucial genes involved in CD8 T cell memory and sensitivity to regulatory elements. J Immunol 181, 299–308.[CrossRef]
    [Google Scholar]
  13. Rist, M., Cooper, L., Elkington, R., Walker, S., Fazou, C., Tellam, J., Crough, T. & Khanna, R. ( 2005; ). Ex vivo expansion of human cytomegalovirus-specific cytotoxic T cells by recombinant polyepitope: implications for HCMV immunotherapy. Eur J Immunol 35, 996–1007.[CrossRef]
    [Google Scholar]
  14. Schluns, K. S. & Lefrancois, L. ( 2003; ). Cytokine control of memory T-cell development and survival. Nat Rev Immunol 3, 269–279.[CrossRef]
    [Google Scholar]
  15. Schluns, K. S., Kieper, W. C., Jameson, S. C. & Lefrancois, L. ( 2000; ). Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nat Immunol 1, 426–432.[CrossRef]
    [Google Scholar]
  16. Schluns, K. S., Williams, K., Ma, A., Zheng, X. X. & Lefrancois, L. ( 2002; ). Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J Immunol 168, 4827–4831.[CrossRef]
    [Google Scholar]
  17. Schluns, K. S., Klonowski, K. D. & Lefrancois, L. ( 2004; ). Transregulation of memory CD8 T-cell proliferation by IL-15Rα + bone marrow-derived cells. Blood 103, 988–994.
    [Google Scholar]
  18. Shedlock, D. J. & Shen, H. ( 2003; ). Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 300, 337–339.[CrossRef]
    [Google Scholar]
  19. Shedlock, D. J., Whitmire, J. K., Tan, J., MacDonald, A. S., Ahmed, R. & Shen, H. ( 2003; ). Role of CD4 T cell help and costimulation in CD8 T cell responses during Listeria monocytogenes infection. J Immunol 170, 2053–2063.[CrossRef]
    [Google Scholar]
  20. Smith, C. M., Wilson, N. S., Waithman, J., Villadangos, J. A., Carbone, F. R., Heath, W. R. & Belz, G. T. ( 2004; ). Cognate CD4+ T cell licensing of dendritic cells in CD8+ T cell immunity. Nat Immunol 5, 1143–1148.[CrossRef]
    [Google Scholar]
  21. Smith, C., Martinez, M., Cooper, L., Rist, M., Zhong, J. & Khanna, R. ( 2008; ). Generating functional CD8+ T cell memory response under transient CD4+ T cell deficiency: implications for vaccination of immunocompromised individuals. Eur J Immunol 38, 1857–1866.[CrossRef]
    [Google Scholar]
  22. Sun, J. C. & Bevan, M. J. ( 2003; ). Defective CD8 T cell memory following acute infection without CD4 T cell help. Science 300, 339–342.[CrossRef]
    [Google Scholar]
  23. Sun, J. C. & Bevan, M. J. ( 2004; ). Cutting edge: long-lived CD8 memory and protective immunity in the absence of CD40 expression on CD8 T cells. J Immunol 172, 3385–3389.[CrossRef]
    [Google Scholar]
  24. Sun, J. C., Williams, M. A. & Bevan, M. J. ( 2004; ). CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection. Nat Immunol 5, 927–933.[CrossRef]
    [Google Scholar]
  25. Tan, J. T., Ernst, B., Kieper, W. C., LeRoy, E., Sprent, J. & Surh, C. D. ( 2002; ). 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 195, 1523–1532.[CrossRef]
    [Google Scholar]
  26. Zhong, J., Rist, M., Cooper, L., Smith, C. & Khanna, R. ( 2008; ). Induction of pluripotent protective immunity following immunisation with a chimeric vaccine against human cytomegalovirus. PLoS ONE 3, e3256.[CrossRef]
    [Google Scholar]
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