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International Immunology Advance Access published online on September 2, 2008
International Immunology, doi:10.1093/intimm/dxn093
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

From the two-dimensional Th1 and Th2 phenotypes to high-dimensional models for gene regulation

Henk-Jan van den Ham and Rob J. de Boer

Theoretical Biology and Bioinformatics, Universiteit Utrecht, Utrecht, The Netherlands

Correspondence to: Correspondence to: H.J. van den Ham; E-mail: h.j.vandenham{at}uu.nl

The Th1/Th2 paradigm has been used for decades to characterize phenotypically different immune responses. Recent discoveries, e.g. Th17 cells are adding more dimensions to the helper T cell framework, and the Th1/Th2 paradigm is currently being extended to include these new phenotypes. Previous mathematical models cannot easily be extended to accommodate these new phenotypes, and therefore these discoveries call for a new type of models. We devised a new model of helper T cell differentiation that describes expression of, and interactions between, the master regulators determining the phenotypic polarization of helper T cells. The model is able to describe any number of master regulators and is grounded on transcription factors binding promoter sites and binding each other. The model allows for stable switches between several different phenotypes. Furthermore, the model accounts for the kinetics of FoxP3 and GATA3 mRNA expression measured after stimulating naive helper (CD4+CD45RA+) T cells under various circumstances. Due to its n-dimensional character, this model may easily be applied to other developmental processes that involve master regulators.

Keywords: helper T cell differentiation, master regulator, mathematical model

Transmitting editor: A. Kelso

Received 10 March 2008, accepted 1 July 2008.


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