An interdisciplinary analysis of inflammatory signalling dynamics in single cells

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An interdisciplinary analysis of inflammatory signalling dynamics in single cells Christopher Boddington (2015) A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy Immune cells must accurately interpret environmental signals to make robust cell fate decisions and control inflammatory signalling.Many signals (e.g.Tumor Necrosis Factor alpha (TNF↵) or interferon gamma (IFN )) converge on just a few key signalling systems such as Nuclear Factor kappa B (NF-B) or Signal Transducers and Activators of Transcription (STAT), which exhibit complex activation dynamics that control patterns of downstream gene expression.Often, seemingly identical cells show heterogeneous or random behaviour to a common stimulus.Therefore, a key question is how can immune cells coordinate inflammatory signalling in the presence of this noise.The NF-B system dynamics were studied in response to rapidly changing inflammatory signals.It was shown that pulsed TNF↵ cytokine stimulations induced digital single-cell NF-B responses, with only a fraction of cells able to respond to repeated pulses.These responses appeared to be reproducible in individual cells, but heterogeneous in the population.Mathematical models of the NF-B signalling network suggested that single-cell responses were governed through a refractory state potentially encoded via 'extrinsic' noise in the levels of signalling molecules related to the TNF↵ signal transduction pathway.Such signal processing enabled robust and reproducible single cell responses and maintained acute tissue-level signalling, with fewer cells responding to shorter pulsing intervals.

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