Dendritic cells differentiated in the presence of a single-stranded viral RNA sequence conserve their ability to activate CD4 T lymphocytes but lose their capacity for Th1 polarization.
Monocyte-derived dendritic cells (DCs) differentiate in the presence of Toll-like-receptor (TLR) ligands in the course of ongoing infections. A single-stranded RNA (ssRNA) sequence, corresponding to the sequence of the U5 region of human immunodeficiency virus type 1 RNA, was used to mimic viral activation of TLR7 in human DCs. We determined the effector potential of DCs differentiated in the presence of this ssRNA molecule (ssRNA-DCs). ssRNA-DCs phenotypically resembled mature DCs. In contrast, their capacity to allostimulate naive CD4(+) T cells resembled that of conventional immature DCs and could be increased by TLR4 stimulation. Th1 polarization of CD4(+) T cells and production of interleukin 12p70 (IL-12p70) by ssRNA-DCs were selectively abrogated in response to a late TLR4, but not in response to a CD40, maturation signal. Inhibition of p38 mitogen-activated protein kinase partially restored IL-12p70 secretion but did not restore Th1 polarization, whereas addition of exogenous IL-12 led to recovery of Th1 polarization. In contrast to lipopolysaccharide, ssRNA induced IL-12p70 production at the very earliest stages of DC differentiation, indicating a particular role for TLR7 in monocyte-derived DCs recently engaged in differentiation. These data demonstrate generation of phenotypically mature DCs with the ability to expand CD4(+) T lymphocytes lacking Th1/2-polarizing capacity.
Marin-Esteban
Viviana
V
Institut National de la Santé et de la Recherche Médicale U662, Paris, France.
Abdul
Mubashira
M
Charron
Dominique
D
Haziot
Alain
A
Mooney
Nuala
N
D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation; D016764:Cell Polarity; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation; D011725:Pyridines / Q000494:pharmacology; D012367:RNA, Viral / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D004791:Enzyme Inhibitors; D007093:Imidazoles; D008070:Lipopolysaccharides; D011725:Pyridines; D012367:RNA, Viral; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D016753:Interleukin-10; D018664:Interleukin-12; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580