title: TLR ligands can activate dendritic cells to provide a MyD88-dependent negative signal for Th2 cell development.
abstract: During infection, CD4(+) Th cell responses polarize to become primarily Th1 or Th2. Th1 cells, which make IFN-gamma, are crucial for immunity to many bacterial and protozoal infections, whereas Th2 cells, which make IL-4, IL-5, and IL-13, are important for resistance to helminth infections. Polarized Th1 responses are induced by dendritic cells (DCs), which respond to pathogen-derived TLR ligands to produce IL-12 and related cytokines that are instrumental in Th1 cell outgrowth, and coordinately process and present Ag in the context of MHC class II to activate naive Th cells. In this study we show that in addition to providing positive signals for Th1 cell development, mouse DCs activated by TLR engagement can also provide a potent negative signal that prevents the development of Th2 cells. Production of this signal, which is not IL-12, IL-18, IL-23, IL-27, or IFN-gamma and is not provided via Th1 cells, is dependent upon a MyD88-dependent, TNF receptor-associated factor-6-independent signaling pathway in DCs. The signal is released from DCs in response to activation via TLR ligands and exerts an effect directly on Th cells rather than through a third-party cell. Our findings indicate that DCs can provide potent negative as well as positive instruction for Th response polarization, and that these instructional signals are distinct and independent.
authors.affiliation: Department of Pathobiology, University of Pennsylvania, Philadelphia 19104, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Sun
authors.forename: Matthew
authors.initials: M
authors.lastname: Walsh
authors.forename: Alejandro V
authors.initials: AV
authors.lastname: Villarino
authors.forename: Laura
authors.initials: L
authors.lastname: Cervi
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Hunter
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Pearce
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D015536:Down-Regulation / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006131:Growth Inhibitors / Q000378:metabolism / Q000502:physiology; D018664:Interleukin-12 / Q000172:deficiency / Q000235:genetics; D053762:Interleukin-12 Subunit p40; D020382:Interleukin-18 / Q000502:physiology; D007378:Interleukins / Q000502:physiology; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D010047:Ovalbumin / Q000276:immunology / Q000378:metabolism; D011425:Propionibacterium acnes / Q000276:immunology; D021122:Protein Subunits / Q000172:deficiency / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D048029:TNF Receptor-Associated Factor 6 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D051193:Toll-Like Receptors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D018984:Epitopes, T-Lymphocyte; D006131:Growth Inhibitors; C486767:Il27 protein, mouse; D053762:Interleukin-12 Subunit p40; D020382:Interleukin-18; D007378:Interleukins; D008024:Ligands; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D021122:Protein Subunits; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D018664:Interleukin-12; D010047:Ovalbumin