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.

journal_name

Sci Rep

journal_title

Scientific reports

authors

Polak ME,Ung CY,Masapust J,Freeman TC,Ardern-Jones MR

doi

10.1038/s41598-017-00651-5

subject

Has Abstract

pub_date

2017-04-06 00:00:00

pages

668

issue

1

issn

2045-2322

pii

10.1038/s41598-017-00651-5

journal_volume

7

pub_type

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