Abstract
Mycobacterium tuberculosis (MTB) persists inside macrophages despite vigorous immune responses. MTB and MTB 19-kDa lipoprotein inhibit class II MHC (MHC-II) expression and Ag processing by a Toll-like receptor 2-dependent mechanism that is shown in this study to involve a defect in IFN-gamma induction of class II transactivator (CIITA). Exposure of macrophages to MTB or MTB 19-kDa lipoprotein inhibited IFN-gamma-induced MHC-II expression, but not IL-4-induced MHC-II expression, by preventing induction of mRNA for CIITA (total, type I, and type IV), IFN regulatory factor-1, and MHC-II. MTB 19-kDa lipoprotein induced mRNA for suppressor of cytokine signaling (SOCS)1 but did not inhibit IFN-gamma-induced Stat1 phosphorylation. Furthermore, the lipoprotein inhibited MHC-II Ag processing in SOCS1(-/-) macrophages. MTB 19-kDa lipoprotein did not inhibit translocation of phosphorylated Stat1 to the nucleus or Stat1 binding to and transactivation of IFN-gamma-sensitive promoter constructs. Thus, MTB 19-kDa lipoprotein inhibited IFN-gamma signaling independent of SOCS1 and without interfering with the activation of Stat1. Inhibition of IFN-gamma-induced CIITA by MTB 19-kDa lipoprotein may allow MTB to evade detection by CD4(+) T cells.
Publication types
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Comparative Study
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Active Transport, Cell Nucleus / immunology
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Adaptor Proteins, Signal Transducing
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Animals
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Antigen Presentation / immunology
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Antigens, Differentiation / physiology
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Bacterial Proteins / pharmacology*
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Carrier Proteins / biosynthesis
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Carrier Proteins / genetics
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Cell Line
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Cell Nucleus / immunology
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Cell Nucleus / metabolism
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Cell Nucleus / microbiology
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology
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Genes, Reporter
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Genetic Vectors
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Histocompatibility Antigens Class II / metabolism
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Humans
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Interferon-gamma / antagonists & inhibitors*
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Interferon-gamma / pharmacology*
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Interleukin-4 / pharmacology
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Intracellular Signaling Peptides and Proteins*
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Lipoproteins / pharmacology*
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Macrophages / immunology
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Macrophages / metabolism
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Macrophages / microbiology
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Membrane Glycoproteins / physiology
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Mice
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Mice, Inbred C3H
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Mice, Inbred C57BL
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Mice, Knockout
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Mycobacterium tuberculosis / immunology*
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Mycobacterium tuberculosis / physiology
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Myeloid Differentiation Factor 88
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Nuclear Proteins*
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Phosphorylation
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Protein Biosynthesis
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Proteins / genetics
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RNA, Messenger / antagonists & inhibitors
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RNA, Messenger / biosynthesis
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Receptors, Cell Surface / physiology
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Receptors, Immunologic / physiology
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Repressor Proteins*
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STAT1 Transcription Factor
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Toll-Like Receptor 2
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Toll-Like Receptors
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Trans-Activators / antagonists & inhibitors*
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Trans-Activators / biosynthesis*
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Trans-Activators / physiology
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Transcription Factors*
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Transfection
Substances
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19 kDa antigen, Mycobacterium
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Adaptor Proteins, Signal Transducing
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Antigens, Differentiation
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Bacterial Proteins
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Carrier Proteins
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DNA-Binding Proteins
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Histocompatibility Antigens Class II
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Intracellular Signaling Peptides and Proteins
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Lipoproteins
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MHC class II transactivator protein
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MYD88 protein, human
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Membrane Glycoproteins
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Nuclear Proteins
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Proteins
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RNA, Messenger
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Receptors, Cell Surface
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Receptors, Immunologic
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Repressor Proteins
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SOCS1 protein, human
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SOCS3 protein, human
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STAT1 Transcription Factor
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STAT1 protein, human
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Socs1 protein, mouse
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Socs3 protein, mouse
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Stat1 protein, mouse
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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TLR2 protein, human
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Toll-Like Receptor 2
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Toll-Like Receptors
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Trans-Activators
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Transcription Factors
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Interleukin-4
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Interferon-gamma