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

Bhanwar Lal Puniya, Robert G. Todd*, Akram Mohammed, Deborah M. Brown, Matteo Barberis, Tomáš Helikar

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


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.

Original languageEnglish
Article number878
Pages (from-to)1-18
Number of pages18
JournalFrontiers in Physiology
Issue numberAUGUST
Publication statusPublished - 2 Aug 2018


We would like to thank Resa Helikar and Robert Moore for providing feedback on the manuscript. This project was supported by NIH grant no. 5R35GM119770-02 to TH and by the SILS Starting Grant of the University of Amsterdam to MB.

FundersFunder number
National Institutes of Health5R35GM119770-02


    • CD4 T cell differentiation
    • Complex T cell phenotypes
    • Cytokine compositions
    • Cytokine dosage
    • Regulation of T cell plasticity
    • T cell plasticity


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