The Toll-like receptor ligand MALP-2 stimulates dendritic cell maturation and modulates proteasome composition and activity.
A 2-kDa synthetic derivative of the macrophage-activating lipopeptide (MALP-2) from Mycoplasma fermentans is a potent inducer of monocytes/macrophages and improves the immunogenicity of antigens co-administered by systemic and mucosal routes. Dendritic cells (DC) are the most potent antigen-presenting cells, which are able to prime naive T cells in vivo. To elucidate the underlying mechanisms of MALP-2 adjuvanticity, we analyzed its activity on bone marrow-derived murine DC. In vitro stimulation of immature murine DC with MALP-2 resulted in the induction of maturation with up-regulated expression of MHC class II, costimulatory (CD80, CD86) and adhesion (CD40, CD54) molecules. MALP-2 also enhances the secretion of cytokines (IL-1alpha, IL-6 and IL-12), and increases DC stimulatory activity on naive and antigen-specific T cells. Further studies demonstrated that MALP-2 treatment of DC results in a dose-dependent shift from the protein pattern of proteasomes to immunoproteasomes (up-regulation of LMP2, LMP7 and MECL1), which correlates with an increased proteolytic activity. Thus, the adjuvanticity of MALP-2 can be mediated, at least in part, by the stimulation of DC maturation, which in turn leads to an improved antigen presentation. Therefore, MALP-2 is a promising molecule for the development of immune therapeutic or prophylactic interventions.
Vaccine Research Group, GBF-German Research Centre for Biotechnology, Braunschweig, Germany.
Claudia
C
Link
Department of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy.
Riccardo
R
Gavioli
Vaccine Research Group, GBF-German Research Centre for Biotechnology, Braunschweig, Germany.
Thomas
T
Ebensen
Department of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy.
Alessandro
A
Canella
Vaccine Research Group, GBF-German Research Centre for Biotechnology, Braunschweig, Germany.
Elena
E
Reinhard
Vaccine Research Group, GBF-German Research Centre for Biotechnology, Braunschweig, Germany.
Carlos A
CA
Guzmán
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D017951:Antigen Presentation; D015703:Antigens, CD / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002454:Cell Differentiation; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D008024:Ligands; D055666:Lipopeptides; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000819:agonists* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009097:Multienzyme Complexes / Q000737:chemistry / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D051193:Toll-Like Receptors; D015854:Up-Regulation
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D008024:Ligands; D055666:Lipopeptides; D008562:Membrane Glycoproteins; D009097:Multienzyme Complexes; D009842:Oligopeptides; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; C106335:macrophage stimulatory lipopeptide 2; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex