In the first part, structure and function of the gene-regulatory network that controls differentiation of type I T-helper (Th1) cells is investigated. By determining the network structure through an iterative process of modelling and experiments, the author shows that Th1 differentiation proceeds in two steps: In the early effector phase, the Th1 master transcription factor T-bet is controlled by an interferon-? dependent positive feedback loop, while in the later phase a second IL-12 dependent feedback maintains T-bet expression. The antigen signal acts as a switch between the two pathways. Moreover, it is shown that only T-bet expression in the late phase is predictive of the success of the differentiation process. Since T-bet expression in the late phase requires IL-12 stimulation, this work uncovers the molecular mechanisms behind the unique role of IL-12 in Th1 differentiation.
In the second part, regulation of the transcription factor NFAT that mediates antigenic stimulation in T-cells is investigated. NFAT is activated by nuclear import upon dephosphorylation of multiple residues. Based on simultaneous measurements of NFAT subcellular localization and phosphorylation, a quantitative mathematical model of the NFAT regulatory network is developed and the underlying design principles are analyzed.
In summary, the study exemplifies the necessity of a dynamic analysis at the systems level to understand complex biological processes.
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