title: Macrophage-derived dendritic cells have strong Th1-polarizing potential mediated by beta-chemokines rather than IL-12.
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.
authors.affiliation: Baylor Institute for Immunology Research, Dallas, TX 75204. Institut Paris-Sud Sur Les Cytokines, Institut National de la Santé et de la Recherche Médicale, Clamart, France.
authors.forename: W
authors.initials: W
authors.lastname: Zou
authors.forename: J
authors.initials: J
authors.lastname: Borvak
authors.forename: F
authors.initials: F
authors.lastname: Marches
authors.forename: S
authors.initials: S
authors.lastname: Wei
authors.forename: P
authors.initials: P
authors.lastname: Galanaud
authors.forename: D
authors.initials: D
authors.lastname: Emilie
authors.forename: T J
authors.initials: TJ
authors.lastname: Curiel
mesh_terms: D015703:Antigens, CD / Q000096:biosynthesis; D000954:Antigens, Surface / Q000096:biosynthesis; D017209:Apoptosis / Q000276:immunology; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen; D018955:CD36 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D016764:Cell Polarity / Q000276:immunology*; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000378:metabolism / Q000502:physiology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D004357:Drug Synergism; D004768:Enterotoxins / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D006801:Humans; D016023:Integrins / Q000096:biosynthesis; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D015847:Interleukin-4 / Q000494:pharmacology; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D019713:Receptors, CCR5 / Q000502:physiology; D019030:Receptors, Vitronectin / Q000096:biosynthesis; D013211:Staphylococcus aureus / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D000954:Antigens, Surface; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018955:CD36 Antigens; C497964:CD86 protein, human; D019742:Chemokines, CC; D004768:Enterotoxins; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D016023:Integrins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D019713:Receptors, CCR5; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; C031818:enterotoxin B, staphylococcal; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017493:Leukocyte Common Antigens