Abstract
Tuberculosis is a major cause of death in mankind and BCG vaccine protects against childhood but not adult tuberculosis. BCG avoids lysosomal fusion in macrophages decreasing peptides required for activating CD4 T cells and Th1 immunity while suppressing the expression of MHC-II by antigen presenting cells (APCs). An in vitro model of antigen presentation showed that ligands for TLR-9, 7, 4 and 1/2 increased the ability of APCs to present antigen-85B of BCG to CD4 T cells, which correlated with an increase in MHC-II expression. TLR-activation led to a down-regulation of MARCH1 ubiquitin ligase which prevents the degradation of MHC-II and decreased IL-10 also contributed to an increase in MHC-II. TLR-activation induced up-regulation of MHC-II was inhibited by the blockade of IRAK, NF-kB, and MAPKs. TLR-7 and TLR-9 ligands had the most effective adjuvant like effect on MHC-II of APCs which allowed BCG vaccine mediated activation of CD4 T cells.
Keywords:
Antigen processing; BCG vaccine; CD80; CD86; Dendritic cells; IL-10; MARCH1 ubiquitin ligase; MHC-II; Macrophage; Toll-like receptor (TLR).
Published by Elsevier Inc.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Acyltransferases / immunology
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Animals
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Antigen Presentation / genetics
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Antigens, Bacterial / immunology
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Antigens, Bacterial / pharmacology
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BCG Vaccine*
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / microbiology
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Cells, Cultured
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Dendritic Cells / immunology*
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Dendritic Cells / microbiology
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Female
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Histocompatibility Antigens Class II / genetics
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Histocompatibility Antigens Class II / metabolism
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Humans
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Interleukin-10 / genetics
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Interleukin-10 / metabolism
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Lipopolysaccharides / pharmacology
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MAP Kinase Signaling System
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Macrophages / immunology*
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Macrophages / microbiology
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Male
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Mice
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Mice, Inbred C57BL
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Mycobacterium tuberculosis / immunology*
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RNA, Small Interfering / genetics
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Toll-Like Receptor 7 / metabolism*
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Toll-Like Receptor 9 / metabolism*
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Tuberculosis / immunology*
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
Substances
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19K antigen, Mycobacterium tuberculosis
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Antigens, Bacterial
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BCG Vaccine
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Histocompatibility Antigens Class II
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Lipopolysaccharides
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RNA, Small Interfering
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Toll-Like Receptor 7
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Toll-Like Receptor 9
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lipoarabinomannan
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Interleukin-10
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Acyltransferases
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antigen 85C, Mycobacterium tuberculosis
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MARCH1 protein, mouse
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Ubiquitin-Protein Ligases