http://repub.eur.nl/res/aut/38473/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/39025/ 2012-10-01T00:00:00Z 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 demethylation. We also show that plasticity is low during the clonal expansion phase, but that helper T cells may adopt alternative phenotypes during a memory response. http://repub.eur.nl/res/pub/27517/ 2010-09-01T00:00:00Z The T helper paradigm is currently being revised from the Th1-Th2 dichotomy to a multi-state paradigm involving a number of different cell phenotypes. Transcriptional profiling using microarrays has been used to study the development of these phenotypes. There is however no clear consensus on how to approach the analysis of this data, especially in the context of cells that are triggered to expand rapidly, and massively change their gene expression pattern.We develop a method we call 'polar score' to identify genes that are related to T helper cell polarization. This method is designed to identify polarizing genes in a set where many genes change expression. To illustrate the use of this technique, we apply it to published T cell microarray data and compare it to conventional analysis methods. With the new method, we find evidence for the existence of IL9 producing T cells ('Th9 cells') that are induced by a combination of TGF Β and IL4. We identify several candidate master regulator genes for this phenotype. Furthermore, treatment with TGF Β and IL12 results in a Treg and Th17 hybrid cell phenotype.