Abstract
Monocyte-derived dendritic cells (MDDCs) activate naive T lymphocytes to induce adaptive immunity, effecting Th1 polarization through IL-12. However, little is known about other potential DC Th1 polarizing mechanisms, or how T cell polarization may be affected by DCs differentiating in, or exposed to, a proinflammatory environment. Macrophages (MPhis) are DC precursors abundant in inflamed tissues, lymph nodes, and tumors. Thus we studied the T cell-activating and -polarizing properties of MPhi-derived DCs (PhiDCs). Monocytes were cultured in MPhi-CSF (M-CSF) to produce MPhis, which were then differentiated into DCs following culture with GM-CSF plus IL-4. PhiDCs activated a significant allogeneic MLR and were significantly better than MDDCs in activating T cells with superantigen. Most strikingly, PhiDCs elicited up to 9-fold more IFN-gamma from naive or Ag-specific T cells compared with MDDCs (with equivalent IL-4 secretion), despite producing up to 9-fold less IL-12. Neutralization of MDDC, but not PhiDC IL-12 significantly inhibited T cell IFN-gamma induction. PhiDCs produced up to 12-fold more beta-chemokines (macrophage-inflammatory protein-1alpha, -1beta, and RANTES) than MDDCs. Ab blockade of CCR5, but not CXC chemokine receptor 4, inhibited T cell IFN-gamma induction by PhiDCs significantly greater than by MDDCs. Thus DCs differentiating from MPhis induce T cell IFN-gamma through beta-chemokines with little or no requirement for IL-12. Myeloid DCs arising from distinct precursor cells may have differing properties, including different mechanisms of Th1 polarization. These data are the first reports of IFN-gamma induction through chemokines by DCs.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antigens, CD / biosynthesis
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Antigens, Surface / biosynthesis
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Apoptosis / immunology
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B7-1 Antigen / biosynthesis
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B7-2 Antigen
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CD36 Antigens / biosynthesis
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / immunology
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Cell Differentiation / immunology
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Cell Polarity / immunology*
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Cells, Cultured
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Chemokines, CC / metabolism
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Chemokines, CC / physiology*
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Dendritic Cells / cytology
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Drug Synergism
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Enterotoxins / immunology
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Epitopes, T-Lymphocyte / immunology
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Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
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Histocompatibility Antigens Class I / biosynthesis
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Humans
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Integrins / biosynthesis
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Intercellular Adhesion Molecule-1 / biosynthesis
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Interferon-gamma / biosynthesis
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Interferon-gamma / metabolism
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Interleukin-10 / metabolism
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Interleukin-12 / biosynthesis
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Interleukin-12 / metabolism
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Interleukin-12 / physiology*
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Interleukin-4 / pharmacology
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Leukocyte Common Antigens / biosynthesis
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Lipopolysaccharide Receptors / biosynthesis
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Lipopolysaccharides / pharmacology
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Lymphocyte Activation
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Macrophage Colony-Stimulating Factor / pharmacology
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Macrophages / cytology
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Macrophages / immunology*
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Macrophages / metabolism
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Membrane Glycoproteins / biosynthesis
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Myeloid Cells / immunology
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Myeloid Cells / metabolism
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Receptors, CCR5 / physiology
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Receptors, Vitronectin / biosynthesis
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Staphylococcus aureus / immunology
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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Th1 Cells / immunology*
Substances
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Antigens, CD
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Antigens, Surface
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B7-1 Antigen
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B7-2 Antigen
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CD36 Antigens
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CD86 protein, human
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Chemokines, CC
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Enterotoxins
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Epitopes, T-Lymphocyte
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Histocompatibility Antigens Class I
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Integrins
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Lipopolysaccharide Receptors
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Lipopolysaccharides
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Membrane Glycoproteins
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Receptors, CCR5
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Receptors, Vitronectin
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integrin alphaVbeta5
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Intercellular Adhesion Molecule-1
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Interleukin-10
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Interleukin-12
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Interleukin-4
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enterotoxin B, staphylococcal
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Macrophage Colony-Stimulating Factor
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Interferon-gamma
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Granulocyte-Macrophage Colony-Stimulating Factor
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Leukocyte Common Antigens