Experimental and mathematical analysis of regulatory networks in T-helper lymphocytes

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This book employs an interdisciplinary approach that merges dynamic quantitative measurements with mathematical modeling to address two key issues in molecular immunology. The first part explores the gene-regulatory network governing the differentiation of type I T-helper (Th1) cells. Through an iterative modeling and experimental process, the author reveals that Th1 differentiation occurs in two phases. In the early effector phase, the Th1 master transcription factor T-bet is regulated by an interferon-? dependent positive feedback loop, while a second IL-12 dependent feedback sustains T-bet expression in the later phase. The antigen signal acts as a switch between these pathways, with late-phase T-bet expression being a predictor of successful differentiation. This highlights the critical role of IL-12 in Th1 differentiation. The second part investigates the regulation of the transcription factor NFAT, which mediates antigenic stimulation in T-cells. NFAT activation occurs through nuclear import following dephosphorylation of multiple residues. By simultaneously measuring NFAT subcellular localization and phosphorylation, a quantitative model of the NFAT regulatory network is developed, analyzing its underlying design principles. Overall, the study underscores the importance of dynamic systems-level analysis in comprehending complex biological processes.