Monophosphoryl lipid A activates both human dendritic cells and T cells.
The induction of dendritic cell (DC) maturation is critical for the induction of Ag-specific T lymphocyte responses and may be essential for the development of human vaccines relying on T cell immunity. In this study, we have investigated the effects of monophosphoryl lipid A (MPL) on human monocyte-derived DC as well as peripheral blood T cells. Calcium mobilization, mitogen-activated protein kinase activation, and the NF-kappaB transcription factor were induced after MPL stimulation of DC and required high doses of MPL (100 microg/ml). Maturation parameters such as production of IL-12 and increases in cell surface expression of HLA-DR, CD80, CD86, CD40, and CD83 were observed following DC treatment with MPL. However, lower levels of IL-12 were induced by MPL when compared with lipopolysaccharide. This is likely to be related to differences in the kinetics of extracellular signal-related kinase 1/2 and p-38 phosphorylation induced by both molecules. Although maturation induced by MPL was weaker when compared with lipopolysaccharide, it appeared to be sufficient to support optimal activation of allogeneic naive CD45RA(+) T cell and anti-tetanus toxoid CD4 T cells. MPL at low doses (5 microg/ml) had no impact on DC maturation, while its addition to DC-T cell cocultures induced full T cell activation. The observed effect was related to the fact that MPL also acts directly on T cells, likely through their Toll-like receptors, by increasing their intracellular calcium and up-regulating their CD40 ligand expression. Together, these data support a model where MPL enhances T cell responses by having an impact on DC and T cells.
Ismaili
Jamila
J
Laboratory of Experimental Immunology, Faculté de Medecine, Universite Libre de Bruxelles, Brussels, Belgium. jismaili@mrc.gm
Rennesson
Joëlle
J
Aksoy
Ezra
E
Vekemans
Johan
J
Vincart
Benoit
B
Amraoui
Zoulikha
Z
Van Laethem
Francois
F
Goldman
Michel
M
Dubois
Patrice M
PM
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000502:physiology; D023201:CD40 Ligand / Q000096:biosynthesis; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000166:cytology; D016853:Muromonab-CD3 / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D000276:Adjuvants, Immunologic; D018106:CD28 Antigens; D017252:CD3 Complex; D007106:Immune Sera; D008050:Lipid A; D016853:Muromonab-CD3; D016328:NF-kappa B; D023201:CD40 Ligand; D020928:Mitogen-Activated Protein Kinases; C048436:monophosphoryl lipid A