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A mechanistic computational model reveals that plasticity of CD4+ T cell differentiation is a function of cytokine composition and dosage

Puniya, B.L., Todd, R.G., Mohammed, A., Brown, D.M., Barberis, Matteo and Helikar, T. (2018) A mechanistic computational model reveals that plasticity of CD4+ T cell differentiation is a function of cytokine composition and dosage Frontiers in Physiology, 9, 878. pp. 1-18.

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CD4+ T cells provide cell-mediated immunity in response to various antigens. During an immune response, naïve CD4+ T cells differentiate into specialized effector T helper (Th1, Th2, and Th17) cells and induced regulatory (iTreg) cells based on a cytokine milieu. In recent studies, complex phenotypes resembling more than one classical T cell lineage have been experimentally observed. Herein, we sought to characterize the capacity of T cell differentiation in response to the complex extracellular environment. We constructed a comprehensive mechanistic (logical) computational model of the signal transduction that regulates T cell differentiation. The model's dynamics were characterized and analyzed under 511 different environmental conditions. Under these conditions, the model predicted the classical as well as the novel complex (mixed) T cell phenotypes that can co-express transcription factors (TFs) related to multiple differentiated T cell lineages. Analyses of the model suggest that the lineage decision is regulated by both compositions and dosage of signals that constitute the extracellular environment. In this regard, we first characterized the specific patterns of extracellular environments that result in novel T cell phenotypes. Next, we predicted the inputs that can regulate the transition between the canonical and complex T cell phenotypes in a dose-dependent manner. Finally, we predicted the optimal levels of inputs that can simultaneously maximize the activity of multiple lineage-specifying TFs and that can drive a phenotype toward one of the co-expressed TFs. In conclusion, our study provides new insights into the plasticity of CD4+ T cell differentiation, and also acts as a tool to design testable hypotheses for the generation of complex T cell phenotypes by various input combinations and dosages. © 2018 Puniya, Todd, Mohammed, Brown, Barberis and Helikar.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
Puniya, B.L.
Todd, R.G.
Mohammed, A.
Brown, D.M.
Helikar, T.
Date : 2 August 2018
Funders : National Institute for Health Research (NIHR)
DOI : 10.3389/fphys.2018.00878
Copyright Disclaimer : © 2018 Puniya, Todd, Mohammed, Brown, Barberis and Helikar. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Uncontrolled Keywords : CD4+ T cell differentiation; Complex T cell phenotypes; Cytokine compositions; Cytokine dosage; Regulation of T cell plasticity; T cell plasticity
Depositing User : Clive Harris
Date Deposited : 11 Apr 2019 09:47
Last Modified : 11 Apr 2019 09:47

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