Abstract
Naive Th cells can be directed in vitro to develop into Th1 or Th2 cells by IL-12 or IL-4, respectively. In vivo, chronic immune reactions lead to polarized Th cytokine patterns. We found earlier that Borrelia burgdorferi, the spirochaete that causes Lyme disease, induces Th1 development in alpha beta TCR-transgenic Th cells. Here, we used TCR-transgenic Th cells and oligonucleotide arrays to analyze the differences between Th1 cells induced by IL-12 vs those induced by B. burgdorferi. Transgenic Th cells primed with peptide in the presence of B. burgdorferi expressed several mRNAs, including the mRNA encoding IL-17, at significantly higher levels than Th cells primed with peptide and IL-12. Cytometric single-cell analysis of Th cell cytokine production revealed that IL-17 cannot be categorized as either Th1 or Th2 cytokine. Instead, almost all IL-17-producing Th cells simultaneously produced TNF-alpha and most IL-17(+) Th cells also produced GM-CSF. This pattern was also observed in humans. Th cells from synovial fluid of patients with Lyme arthritis coexpressed IL-17 and TNF-alpha upon polyclonal stimulation. The induction of IL-17 production in Th cells is not restricted to B. burgdorferi. Priming of TCR-transgenic Th cells in the presence of mycobacterial lysates also induced IL-17/TNF-alpha coproduction. The physiological stimulus for IL-17 production was hitherto unknown. We show here for the first time that microbial stimuli induce the expression of IL-17 together with TNF-alpha in both murine and human T cells. Chronic IL-17 expression induced by microbes could be an important mediator of infection-induced immunopathology.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arthritis, Reactive / immunology
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Bacterial Proteins / chemical synthesis
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Bacterial Proteins / immunology*
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Borrelia burgdorferi Group / immunology*
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD4-Positive T-Lymphocytes / microbiology
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cells, Cultured
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Chemokines / biosynthesis
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Chemokines / genetics
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Cytokines / biosynthesis
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Cytokines / genetics
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Granulocyte-Macrophage Colony-Stimulating Factor / biosynthesis
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Humans
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Immunophenotyping
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Interleukin-12 / physiology
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Interleukin-17 / biosynthesis*
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Interleukin-18 / physiology
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Interleukin-6 / physiology
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Lipoproteins / chemical synthesis
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Lipoproteins / immunology*
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Lyme Disease / immunology
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Lymphocyte Activation / genetics
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Mice
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Mice, Inbred BALB C
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Mice, Transgenic
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Peptides / chemical synthesis
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Peptides / immunology*
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RNA, Messenger / biosynthesis
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Receptors, Antigen, T-Cell, alpha-beta / genetics
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Synovial Fluid / cytology
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Synovial Fluid / immunology
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Synovial Fluid / metabolism
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Synovial Fluid / microbiology
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocyte Subsets / microbiology
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T-Lymphocytes, Helper-Inducer / cytology
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T-Lymphocytes, Helper-Inducer / immunology*
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T-Lymphocytes, Helper-Inducer / metabolism*
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T-Lymphocytes, Helper-Inducer / microbiology
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Th1 Cells / immunology
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Th1 Cells / metabolism
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Th2 Cells / immunology
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Th2 Cells / metabolism
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Tumor Necrosis Factor-alpha / biosynthesis
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Up-Regulation / genetics
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Up-Regulation / immunology
Substances
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Bacterial Proteins
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Chemokines
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Cytokines
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Interleukin-17
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Interleukin-18
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Interleukin-6
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Lipoproteins
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Peptides
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RNA, Messenger
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Receptors, Antigen, T-Cell, alpha-beta
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Tumor Necrosis Factor-alpha
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Interleukin-12
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Granulocyte-Macrophage Colony-Stimulating Factor