title: Petri Net computational modelling of Langerhans cell Interferon Regulatory Factor Network predicts their role in T cell activation.
abstract: Langerhans cells (LCs) are able to orchestrate adaptive immune responses in the skin by interpreting the microenvironmental context in which they encounter foreign substances, but the regulatory basis for this has not been established. Utilising systems immunology approaches combining in silico modelling of a reconstructed gene regulatory network (GRN) with in vitro validation of the predictions, we sought to determine the mechanisms of regulation of immune responses in human primary LCs. The key role of Interferon regulatory factors (IRFs) as controllers of the human Langerhans cell response to epidermal cytokines was revealed by whole transcriptome analysis. Applying Boolean logic we assembled a Petri net-based model of the IRF-GRN which provides molecular pathway predictions for the induction of different transcriptional programmes in LCs. In silico simulations performed after model parameterisation with transcription factor expression values predicted that human LC activation of antigen-specific CD8 T cells would be differentially regulated by epidermal cytokine induction of specific IRF-controlled pathways. This was confirmed by in vitro measurement of IFN-γ production by activated T cells. As a proof of concept, this approach shows that stochastic modelling of a specific immune networks renders transcriptome data valuable for the prediction of functional outcomes of immune responses.
authors.affiliation: Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, SO16 6YD, Southampton, UK. m.e.polak@soton.ac.uk.|Institute for Life Sciences, University of Southampton, SO17 1BJ, Southampton, UK. m.e.polak@soton.ac.uk.
authors.forename: Marta E
authors.identifier: http://orcid.org/0000-0003-2878-476X
authors.initials: ME
authors.lastname: Polak
authors.affiliation: Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, SO16 6YD, Southampton, UK.
authors.forename: Chuin Ying
authors.initials: CY
authors.lastname: Ung
authors.affiliation: Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, SO16 6YD, Southampton, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Masapust
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Edinburgh, Midlothian, EH25 9RG, UK.
authors.forename: Tom C
authors.initials: TC
authors.lastname: Freeman
authors.affiliation: Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, SO16 6YD, Southampton, UK.
authors.forename: Michael R
authors.identifier: http://orcid.org/0000-0003-1466-2016
authors.initials: MR
authors.lastname: Ardern-Jones
mesh_terms: D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D019295:Computational Biology / Q000379:methods; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D063990:Gene Ontology; D053263:Gene Regulatory Networks; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D007801:Langerhans Cells / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology*; D008954:Models, Biological; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D050835:Interferon Regulatory Factors