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Data-driven modeling of T cell activation

Schulze, Anna

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T cells accurately discriminate between antigens that have only moderately different affinities. The decision of whether the cell is activated or not is made during the initial stages of membrane-proximal signaling triggered by the T cell receptor (TCR). Several mechanistic models have been proposed to explain the highly specific and sensitive recognition of peptide-MHC ligands. Prominent among them is the kinetic proofreading model that accounts for the high specificity of the ligand discrimination by the TCR based on ligand dwell time. Open questions of central importance are (1) whether kinetic proofreading is indeed realized in TCR signal transduction and (2) how information about ligand binding to the TCR is transduced to the cell interior. In this work, we addressed these questions quantitatively by means of two data–based models. Our models describe the dynamics of two core modules of TCR activation: the TCR signaling module and the Src–family kinase regulation module. The model of TCR signaling accounts for the reversible phosphorylation of im- munoreceptor tyrosine–based activation motifs (ITAMs) in the TCR complex by the kinase Lck and the phosphatase CD45, and the subsequent recruitment and phosphorylation of the pivotal kinase ZAP70. We parameterize the model using ki- netic measurements of phosphorylation status and protein-protein interactions. The model constrained by these data allows for kinetic proofreading of ligand dwell time; however, this capacity depends on the mechanism of signal initiation. Neither an enhancement of phosphorylation nor a reduction of phosphatase activity alone allow the TCR to discriminate ligand dwell times, whereas a combination of both effects yields kinetic proofreading behavior. TCR signaling is driven by the Src–family kinase Lck: thus we investigated the dynamic regulation of Lck activity in the second model. The parameterization of this model is based on dose–response data of wild type Lck and Lck chimeras with altered membrane targeting. These data allow us to determine the model parameters within narrow confidence bounds enabling us to make quantitative predictions with the model. We find that Lck activity is regulated jointly by its subcellular localization, trans–autophosphorylation of the activating tyrosine residue and the activity of the phosphatase CD45 in the proximity of Lck. Mechanistically, CD45 mediates both activating and inhibitory dephosphorylations of Lck. Physiologically, we find that CD45 has a solely inhibitory effect on Lck activity. Interestingly, this inhibitory action could synergize with the mechanisms modeled in the TCR signaling model to support kinetic proofreading. In summary, our results show how data-driven mathematical modeling, can be used to dissect the complexity of TCR activation on a quantitative basis.

Item Type: Dissertation
Supervisor: Höfer, Prof. Dr. Thomas
Date of thesis defense: 24 June 2014
Date Deposited: 01 Sep 2014 08:45
Date: 2014
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 500 Natural sciences and mathematics
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