A Push-Pull Approach to Maximize Vaccine Efficacy: Abrogating Suppression with an IL-13 Inhibitor While Augmenting Help with Granulocyte/Macrophage Colony-Stimulating Factor and CD40L

Although a role for CD4+helper cells in CD8+cytotoxic T lymphocyte (CTL) induction by vaccines is widely recognized, much less is known about a counterbalancing role of CD4+T cells in down-modulating this response, or about ways to optimize vaccine responses through abrogation of this negative regul...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2002-10, Vol.99 (20), p.13020-13025
Main Authors: Ahlers, Jeffrey D., Belyakov, Igor M., Terabe, Masaki, Koka, Rima, Donaldson, Debra D., Thomas, Elaine K., Berzofsky, Jay A.
Format: Article
Language:English
Subjects:
AIDS
Analysis of Variance
Animals
Biological Sciences
CD4-Positive T-Lymphocytes - metabolism
CD40 Ligand - metabolism
CD8-Positive T-Lymphocytes - metabolism
Cellular immunity
Cytokines
Dimerization
Epitopes
Female
Granulocyte-Macrophage Colony-Stimulating Factor - metabolism
Immunization
Interleukin-13 - antagonists & inhibitors
Interleukin-13 - metabolism
Mice
Mice, Inbred BALB C
Natural killer T cells
Spleen cells
T lymphocytes
T-Lymphocytes, Cytotoxic - metabolism
Vaccination
Vaccines, Synthetic - immunology
Vaccinia virus - genetics
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Summary:Although a role for CD4+helper cells in CD8+cytotoxic T lymphocyte (CTL) induction by vaccines is widely recognized, much less is known about a counterbalancing role of CD4+T cells in down-modulating this response, or about ways to optimize vaccine responses through abrogation of this negative regulatory mechanism. Here, we discovered a synergistic enhancement of vaccine-mediated CTL induction and protection by the relief of suppression through depletion of regulatory CD4+cells, including CD4+NKT cells, or blockade of IL-13 made by these cells, combined with the cytokine granulocyte/macrophage colony-stimulating factor and the costimulatory molecule CD40L. Indeed, in the absence of helper epitopes, granulocyte/macrophage colony-stimulating factor and the helper-mimetic molecule CD40L are not sufficient to replace help to induce CTL without abrogation of CD4+T cell-mediated suppression, suggesting a role for T cell help in overcoming suppression. The increased CTL induction translated to striking protection against viral infection by a vaccine by using this synergistic combined approach. These results argue for a push-pull approach to maximize vaccine efficacy, especially for HIV and cancer.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.192251199