CpG-C immunostimulatory oligodeoxyribonucleotide activation of plasmacytoid dendritic cells in rhesus macaques to augment the activation of IFN-gamma-secreting simian immunodeficiency virus-specific T cells.
There are two principle subsets of dendritic cells (DCs); CD11c(+)CD123(-) myeloid DCs (MDCs) and CD11c(-)CD123(+) plasmacytoid DCs (PDCs). DC activation via TNF-TNFRs (e.g., CD40L) and TLRs (e.g., immunostimulatory oligodeoxyribonucleotides (ISS-ODNs)) is crucial for maximal stimulation of innate and adaptive immunity. Macaque DC biology is being studied to improve HIV vaccines using the SIV macaque model. Using lineage (Lin) markers to exclude non-DCs, Lin(-)HLA-DR(+)CD11c(+)CD123(-) MDCs and Lin(-)HLA-DR(+)CD11c(-)CD123(+) PDCs were identified in the blood of uninfected macaques and healthy macaques infected with SIV or simian-human immunodeficiency virus. Overnight culture of DC-enriched Lin-depleted cells increased CD80 and CD86 expression. IL-12 production and CD80/CD86 expression by MDC/PDC mixtures was further enhanced by CD40L and ISS-ODN treatment. A CpG-B ISS-ODN increased CD80/CD86 expression by PDCs, but resulted in little IFN-alpha secretion unless IL-3 was added. In contrast, a CpG-C ISS-ODN and aldrithiol-2-inactivated (AT-2) SIV induced considerable PDC activation and IFN-alpha release without needing exogenous IL-3. The CpG-C ISS-ODN also stimulated IL-12 release (unlike AT-2 SIV) and augmented DC immunostimulatory activity, increasing SIV-specific T cell IFN-gamma production induced by AT-2 SIV-presenting MDC/PDC-enriched mixtures. These data highlight the functional capacities of MDCs and PDCs in naive as well as healthy, infected macaques, revealing a promising CpG-C ISS-ODN-driven DC activation strategy that boosts immune function to augment preventative and therapeutic vaccine efficacy.
Teleshova
Natalia
N
Center for Biomedical Research, Population Council, New York, NY 10021, USA.
Kenney
Jessica
J
Jones
Jennifer
J
Marshall
Jason
J
Van Nest
Gary
G
Dufour
Jason
J
Bohm
Rudolf
R
Lifson
Jeffrey D
JD
Gettie
Agegnehu
A
Pope
Melissa
M
D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives* / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D039521:CD11c Antigen / Q000032:analysis; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000145:classification / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D004220:Disulfides / Q000494:pharmacology; D005260:Female; D016898:Interferon-alpha / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism; D007377:Interleukin-3 / Q000494:pharmacology; D053650:Interleukin-3 Receptor alpha Subunit; D008213:Lymphocyte Activation / Q000276:immunology*; D008253:Macaca mulatta; D008297:Male; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000494:pharmacology*; D009841:Oligonucleotides / Q000276:immunology / Q000494:pharmacology*; D016185:Receptors, Interleukin-3 / Q000032:analysis; D018449:SAIDS Vaccines / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D015164:Vaccines, Inactivated / Q000276:immunology
D000276:Adjuvants, Immunologic; C474878:C274 oligonucleotide; D039521:CD11c Antigen; D004220:Disulfides; C115022:IL3RA protein, human; D016898:Interferon-alpha; D007377:Interleukin-3; D053650:Interleukin-3 Receptor alpha Subunit; D009838:Oligodeoxyribonucleotides; D009841:Oligonucleotides; D016185:Receptors, Interleukin-3; D018449:SAIDS Vaccines; D015164:Vaccines, Inactivated; D018664:Interleukin-12; C001105:2,2'-dipyridyl disulfide; C489630:1018 oligonucleotide; D015082:2,2'-Dipyridyl; D007371:Interferon-gamma