title: Human CD8⁺ T cells drive Th1 responses through the differentiation of TNF/iNOS-producing dendritic cells.
abstract: TNF/iNOS-producing dendritic cells (Tip-DCs) have been shown to arise during inflammation and are important mediators of immune defense. However, it is still relatively unclear which cell types contribute to their differentiation. Here we show that CD8(+) T cells, through the interaction with DCs, can induce the rapid development of human monocytes into Tip-DCs that express high levels of TNF-α and iNOS. Tip-DCs exhibited T-cell priming ability, expressed high levels of MHC class II, upregulated co-stimulatory molecules CD40, CD80, CD86, toll-like receptors TLR2, TLR3, TLR4, chemokine receptors CCR1 and CX3CR1 and expressed the classical mature DC marker, CD83. Differentiation of monocytes into Tip-DCs was partially dependent on IFN-γ as blocking the IFN-γ receptor on monocytes resulted in a significant decrease in CD40 and CD83 expression and in TNF-α production. Importantly, these Tip-DCs were capable of further driving Th1 responses by priming naive CD4(+) T cells for proliferation and IFN-γ production and this was partially dependent on Tip-DC production of TNF-α and NO. Our study hence identifies a role for CD8(+) T cells in orchestrating Th1-mediating signals through the differentiation of monocytes into Th1-inducing Tip-DCs.
authors.affiliation: Immunology Programme and Department of Microbiology, National University of Singapore, Singapore.
authors.forename: Shu Zhen
authors.initials: SZ
authors.lastname: Chong
authors.forename: Kok Loon
authors.initials: KL
authors.lastname: Wong
authors.forename: Gen
authors.initials: G
authors.lastname: Lin
authors.forename: Christopher Maolin
authors.initials: CM
authors.lastname: Yang
authors.forename: Siew-Cheng
authors.initials: SC
authors.lastname: Wong
authors.forename: Veronique
authors.initials: V
authors.lastname: Angeli
authors.forename: Paul A
authors.initials: PA
authors.lastname: Macary
authors.forename: David Michael
authors.initials: DM
authors.lastname: Kemeny
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000073883:CX3C Chemokine Receptor 1; D002450:Cell Communication / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II / Q000276:immunology / Q000378:metabolism*; D054389:Receptors, CCR1 / Q000096:biosynthesis; D019707:Receptors, Chemokine / Q000096:biosynthesis; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D051193:Toll-Like Receptors / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*
chemical_list: D019138:Antibodies, Blocking; D015703:Antigens, CD; C515300:CCR1 protein, human; D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D000949:Histocompatibility Antigens Class II; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II