A computational analysis of signal transduction pathways and transcriptional factors in T lymphocytes.

摘要

T cells are important elements in the immune system. T cell receptor is responsible for initiating the signaling events, which depending on the magnitude and duration of the signal. T cell receptor stimulation initiates a cascade of reactions that leads to nuclear localization signals exposed on both NFAT and NFkappaB allowing translocation of their free and transcriptionally active forms to the nucleus where they can promote gene transcription. The focus of the dissertation work is to study key elements required for triggering T cell activation and find key points that control mechanisms and regulation of T cell activation through the development of a series of integrated models for calcium dynamics, NFAT pathways and NFkappaB pathways. The model suggests that translocation of transcription factors to the nucleus is controlled by calcium signaling, and Ca2+ influx through Ca2+ release-activated Ca2+ CRAC channels is required for T cells activation. The model also suggests that mitochondria reside close to CRAC channels where they regulate the activation of CRAC channels. The end result is the first such model that integrates physiological responses to gene expression in T cells. The model suggests that the negative feedback of cytosolic Ca 2+ and diacylglycerol (DAG) through PKC on phospholipase C (PLC) can give rise to oscillations in IP3 and DAG in T cells but that the oscillations in IP3 are not necessary for oscillations in cytosolic Ca2+. Furthermore, the model simulates the experimental finding that Ca2+ activated PLC seen in other cell types and suggests that this positive feedback of Ca2+ does not play is not a requirement for the experimentally observed Ca2+ and DAG dynamics in these other cell types.