Student Presentation: Edda Schultz, Luca Mariani

Title

Modeling regulatory mechanisms in T helper lymphocytes: Activation, differentiation and memory.

Presenters

Edda Schultz and Luca Mariani

Abstract

T-helper (Th) lymphocytes regulate adaptive immune responses through the secretion of cytokines. According to the nature of the pathogen, undifferentiated Th cells are instructed to become Th1 or Th2 cells by stimulation with their cognate antigen and the differentiation signals, IL-12 and IL-4 respectively. The mechanisms underlying instruction and maintenance of these phenotypes are controlled by complex gene-regulatory networks and changes in chromatin accessibility. To deduce the structure of the gene-regulatory network underlying Th1 differentiation, we systematically perturbed its main regulators and measured the altered expression kinetics of key genes. Through construction of an ODE-model that can reproduce the expression kinetics quantitatively, we found that the network structure evolves over time in a highly dynamic manner. The checkpoints of Th1 differentiation, like S-phase of the cell cycle and antigenic stimulation, reshape the structure of the network. Interestingly, the Th1/Th2 gene-regulatory network exhibits robust behavior on the population level although cytokines are expressed in a highly stochastic manner by the single cell. In another project we focus on the regulation of Interleukin-4 which is known to be expressed mono-allelically with low probability by Th2 cells. To quantify the noise properties of IL-4 production, expression kinetics were measured after activation at different stages of Th2 differentiation. Using a stochastic model, the observed fluctuations in IL-4 protein are explained by a multi-step process of gene induction, with the opening of chromatin structure and the assembly of the transcription initiation complex as sequential random events. During Th2 differentiation, the progressive increase of the fraction of IL-4 producing cells originates from a higher accessibility of the IL-4 locus. With these examples we show that strength and timing of Th activation are crucial for several physiological tasks and mirror the progress of differentiation. Furthermore, through the presented mathematical models we can quantitatively understand regulatory systems at multiple levels of the immune response.

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