title: 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.
abstract: 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.
authors.affiliation: Molecular Immunogenetics and Vaccine Research Section, Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Ahlers
authors.forename: Igor M
authors.initials: IM
authors.lastname: Belyakov
authors.forename: Masaki
authors.initials: M
authors.lastname: Terabe
authors.forename: Rima
authors.initials: R
authors.lastname: Koka
authors.forename: Debra D
authors.initials: DD
authors.lastname: Donaldson
authors.forename: Elaine K
authors.initials: EK
authors.lastname: Thomas
authors.forename: Jay A
authors.initials: JA
authors.lastname: Berzofsky
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D019281:Dimerization; D000939:Epitopes; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D018793:Interleukin-13 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D014614:Vaccines, Synthetic / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics
chemical_list: D000939:Epitopes; D018793:Interleukin-13; D014614:Vaccines, Synthetic; D023201:CD40 Ligand; D016178:Granulocyte-Macrophage Colony-Stimulating Factor