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Published online before print March 25, 2008

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(Journal of Leukocyte Biology. 2008;83:1530-1540.)
© 2008 by Society for Leukocyte Biology

Maturation of dendritic cells for enhanced activation of anti-HIV-1 CD8⁺ T cell immunity

Graduate School of Public Health and School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

¹Correspondence: University of Pittsburgh Graduate School of Public Health, A419 Crabtree Hall, 130 DeSoto Street, Pittsburgh, PA 15261, USA. E-mail: rinaldo{at}pitt.edu

ABSTRACT

Maturation of dendritic cells (DC) to enhance their capacity to activate T cell immunity to HIV-1 is a key step in immunotherapy of HIV-1 infection with DC. We compared maturation of DC derived from HIV-1-uninfected subjects and infected subjects on antiretroviral therapy (ART) or ART naïve by CD40 ligand (CD40L) and combinations of TLR3 ligand polyinosinic:polycytidylic acid [poly(I:C)] and inflammatory cytokines IFN-, IFN-, IL-1β, and TNF-. The greatest levels of virus-specific IFN- production by CD8⁺ T cells were stimulated by DC treated with CD40L, followed by DC treated with the poly(I:C)-cytokine combination. The highest levels of IL-12p70 were produced by DC treated with CD40L + IFN-, followed by CD40L and the poly(I:C)-cytokine combination. Neutralization of IL-12p70 indicated that it was only partially involved in direct enhancement of antiviral CD8⁺ T cell activity. DC stimulation of antiviral CD8⁺ T cell reactivity was enhanced by activated CD4⁺ T cells at low concentrations but was suppressed at higher CD4⁺ T cell concentrations. Maturation of DC with CD40L obviated the need for CD4⁺ T cell help and overcame this suppressive activity. Finally, we showed that DC from HIV-1-infected subjects on ART, which were treated with the poly(I:C)-cytokine combination, retained the capacity to produce IL-12p70 and activate anti-HIV-1 CD8⁺ T cell responses after restimulation with CD40L, with or without IFN-. Thus, DC from HIV-1-infected subjects can be engineered with CD40L or a poly(I:C)-cytokine combination for enhancing CD8⁺ T cell responses to HIV-1, which has potential applications in HIV-1 immunotherapy.

Key Words: immunotherapy • CD40 ligand • TLR 3 ligand • interferon • CD4 T cells

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