Cell division curtails helper phenotype plasticity and expedites helper T-cell differentiation

Immunology and Cell Biology
H J van den Ham, Rob J de Boer

Abstract

Following activation by antigen, helper T cells differentiate into one of many effector phenotypes. Formulating mechanistic mathematical models combining regulatory networks at the transcriptional, translational and epigenetic level, we study how individual helper T cells may adopt their different phenotypes. For each cytokine phenotype, for example, T helper type 1 (Th1) and type 2 (Th2) cells, we find that the intracellular molecular network allows a cell to adopt one of the three states, which we interpret as naive, active and memory states. Cell division markedly speeds up the differentiation into a particular memory state because of DNA demythelation. In a memory state, cells readily resume production of the same cytokine they produced before. Using stochastic models we show that helper T-cell plasticity (that is, the ability to switch phenotype) is low during clonal expansion. Although most memory cells rapidly secrete the original cytokine upon restimulation, some adopt another phenotype and produce different cytokines, allowing for considerable diversity in the phenotypes that are adopted during a memory response. In summary, we show that helper T-cell division expedites cell differentiation by increasing DNA demethylat...Continue Reading

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Citations

Aug 27, 2014·Journal of Pharmacokinetics and Pharmacodynamics·Penelope A MorelNatasa Miskov-Zivanov
Feb 16, 2016·Nature Reviews. Immunology·Michel DuPage, Jeffrey A Bluestone
Feb 26, 2013·European Journal of Immunology·Henk-Jan van den HamArno C Andeweg
Feb 13, 2015·Frontiers in Bioengineering and Biotechnology·Wassim Abou-JaoudéDenis Thieffry
Jun 20, 2015·PLoS Computational Biology·Mariana Esther Martinez-SanchezElena R Alvarez-Buylla
Jul 25, 2014·Genome Biology and Evolution·Enrico Sandro Colizzi, Paulien Hogeweg

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