title: A systems biology approach to the analysis of subset-specific responses to lipopolysaccharide in dendritic cells.
abstract: Dendritic cells (DCs) are critical for regulating CD4 and CD8 T cell immunity, controlling Th1, Th2, and Th17 commitment, generating inducible Tregs, and mediating tolerance. It is believed that distinct DC subsets have evolved to control these different immune outcomes. However, how DC subsets mount different responses to inflammatory and/or tolerogenic signals in order to accomplish their divergent functions remains unclear. Lipopolysaccharide (LPS) provides an excellent model for investigating responses in closely related splenic DC subsets, as all subsets express the LPS receptor TLR4 and respond to LPS in vitro. However, previous studies of the LPS-induced DC transcriptome have been performed only on mixed DC populations. Moreover, comparisons of the in vivo response of two closely related DC subsets to LPS stimulation have not been reported in the literature to date. We compared the transcriptomes of murine splenic CD8 and CD11b DC subsets after in vivo LPS stimulation, using RNA-Seq and systems biology approaches. We identified subset-specific gene signatures, which included multiple functional immune mediators unique to each subset. To explain the observed subset-specific differences, we used a network analysis approach. While both DC subsets used a conserved set of transcription factors and major signalling pathways, the subsets showed differential regulation of sets of genes that 'fine-tune' the network Hubs expressed in common. We propose a model in which signalling through common pathway components is 'fine-tuned' by transcriptional control of subset-specific modulators, thus allowing for distinct functional outcomes in closely related DC subsets. We extend this analysis to comparable datasets from the literature and confirm that our model can account for cell subset-specific responses to LPS stimulation in multiple subpopulations in mouse and man.
authors.affiliation: Centenary Institute of Cancer Medicine and Cell Biology, New South Wales, Australia; The Discipline of Dermatology, University of Sydney, New South Wales, Australia.
authors.forename: David G
authors.initials: DG
authors.lastname: Hancock
authors.affiliation: Centenary Institute of Cancer Medicine and Cell Biology, New South Wales, Australia; The Discipline of Dermatology, University of Sydney, New South Wales, Australia.
authors.forename: Elena
authors.initials: E
authors.lastname: Shklovskaya
authors.affiliation: Centenary Institute of Cancer Medicine and Cell Biology, New South Wales, Australia; The Discipline of Dermatology, University of Sydney, New South Wales, Australia.
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Guy
authors.affiliation: Centre for Microbial Diseases & Immunity Research, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Reza
authors.initials: R
authors.lastname: Falsafi
authors.affiliation: Centre for Microbial Diseases & Immunity Research, University of British Columbia, Vancouver, British Columbia, Canada; James Hogg Research Centre, University of British Columbia, St. Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Chris D
authors.initials: CD
authors.lastname: Fjell
authors.affiliation: Centenary Institute of Cancer Medicine and Cell Biology, New South Wales, Australia.
authors.forename: William
authors.initials: W
authors.lastname: Ritchie
authors.affiliation: Centre for Microbial Diseases & Immunity Research, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Robert E W
authors.initials: RE
authors.lastname: Hancock
authors.affiliation: Centenary Institute of Cancer Medicine and Cell Biology, New South Wales, Australia; The Discipline of Dermatology, University of Sydney, New South Wales, Australia.
authors.forename: Barbara
authors.initials: B
authors.lastname: Fazekas de St Groth
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000096:biosynthesis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects; D007108:Immune Tolerance; D007109:Immunity / Q000187:drug effects*; D016130:Immunophenotyping; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D049490:Systems Biology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000276:immunology
chemical_list: D039481:CD11b Antigen; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4