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Plos Biology : Modeling T Cell Antigen Discrimination Based on Feedback Control of Digital Erk Responses, Volume 3

By Marrack, Philippa

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Book Id: WPLBN0003924090
Format Type: PDF eBook :
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Reproduction Date: 2015

Title: Plos Biology : Modeling T Cell Antigen Discrimination Based on Feedback Control of Digital Erk Responses, Volume 3  
Author: Marrack, Philippa
Volume: Volume 3
Language: English
Subject: Journals, Science, Biology
Collections: Periodicals: Journal and Magazine Collection (Contemporary), PLoS Biology
Publication Date:
Publisher: Plos


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Marrack, P. (n.d.). Plos Biology : Modeling T Cell Antigen Discrimination Based on Feedback Control of Digital Erk Responses, Volume 3. Retrieved from

Description : T-lymphocyte activation displays a remarkable combination of speed, sensitivity, and discrimination in response to peptide–major histocompatibility complex (pMHC) ligand engagement of clonally distributed antigen receptors (T cell receptors or TCRs). Even a few foreign pMHCs on the surface of an antigen-presenting cell trigger effective signaling within seconds, whereas 13105–13106 self-pMHC ligands that may differ from the foreign stimulus by only a single amino acid fail to elicit this response. No existing model accounts for this nearly absolute distinction between closely related TCR ligands while also preserving the other canonical features of T-cell responses. Here we document the unexpected highly amplified and digital nature of extracellular signal-regulated kinase (ERK) activation in T cells. Based on this observation and evidence that competing positive- and negative-feedback loops contribute to TCR ligand discrimination, we constructed a new mathematical model of proximal TCR-dependent signaling. The model made clear that competition between a digital positive feedback based on ERK activity and an analog negative feedback involving SH2 domain-containing tyrosine phosphatase (SHP-1) was critical for defining a sharp liganddiscrimination threshold while preserving a rapid and sensitive response. Several nontrivial predictions of this model, including the notion that this threshold is highly sensitive to small changes in SHP-1 expression levels during cellular differentiation, were confirmed by experiment. These results combining computation and experiment reveal that ligand discrimination by T cells is controlled by the dynamics of competing feedback loops that regulate a high-gain digital amplifier, which is itself modulated during differentiation by alterations in the intracellular concentrations of key enzymes. The organization of the signaling network that we model here may be a prototypic solution to the problem of achieving ligand selectivity, low noise, and high sensitivity in biological responses.


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