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Overcoming CD4 deficiency to induce long-lived memory CD8+ CTL

One critical hurdle for therapeutic HIV vaccines is the deficiency of CD4+ T cell help during HIV infection. CD4+ T cell help has been shown to be necessary for induction of long-lived memory CD8+ cytotoxic T lymphocytes (CTL), and when CD8+ T cells are primed in its absence, they are susceptible to TRAIL-mediated death during secondary stimulation. We have found that IL-15 expression by a vaccine vector allowed induction of longer-lived, higher avidity memory CTL. We also observed that CD40L, a molecule by which helper T cells mediate help, induces dendritic cells to secrete IL-15. We therefore hypothesized that one mechanism by which CD4+ T helper cells induce longer-lived memory CTL may be to stimulate IL-15 production by the dendritic cell presenting antigen, and that therefore, IL-15 might overcome the need for CD4+ T cell help. We have now tested this hypothesis by demonstrating that immunization of CD4-depleted mice with a recombinant vaccinia-HIV vaccine vector expressing IL-15 induced long-lived memory CTL, whereas immunization of the depleted mice with a recombinant vaccinia-HIV vector not expressing IL-15 resulted in short-lived CTL that disappeared within two months. Further, CTL induced with the IL-15-expressing vaccine were resistant to TRAIL-mediated death on secondary stimulation, whereas those induced without IL-15 underwent apoptosis. Resistance was associated with upregulation by IL-15 of anti-apoptotic Bcl-XL and downregulation of Bax, a downstream transducer of the TRAIL death signal. These findings help explain the role of helper T cells in inducing long-lived memory CTL and provide a practical approach to overcome the deficiency of CD4+ T cell help during HIV infection for induction of CTL with a therapeutic vaccine for HIV, or with a vaccine for other opportunistic infections.

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Correspondence to Jay A Berzofsky.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Oh, S., Perera, L.P., Waldmann, T.A. et al. Overcoming CD4 deficiency to induce long-lived memory CD8+ CTL. Retrovirology 3, S17 (2006). https://doi.org/10.1186/1742-4690-3-S1-S17

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Keywords

  • Dendritic Cell
  • Therapeutic Vaccine
  • High Avidity
  • Vaccine Vector
  • Dendritic Cell Present Antigen