Maturation of dendritic cells for enhanced activation of anti-HIV-1 CD8(+) T cell immunity.
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-gamma, IFN-alpha, IL-1beta, and TNF-alpha. The greatest levels of virus-specific IFN-gamma 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-gamma, 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-gamma. 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.
Huang
Xiao-Li
XL
Graduate School of Public Health and School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Fan
Zheng
Z
Borowski
LuAnn
L
Rinaldo
Charles R
CR
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000276:immunology; D023201:CD40 Ligand / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000502:physiology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis / Q000494:pharmacology; D008213:Lymphocyte Activation; D051196:Toll-Like Receptor 3 / Q000502:physiology
C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma