ArticleScience signaling2013
The duration of T cell stimulation is a critical determinant of cell fate and plasticity.
Article in Science signaling, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 115 citations in OpenAlex.
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- Spatial presentation of biological molecules to cells by localized diffusive transfer.Lab on a chip · 2019Article
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- An enriched network motif family regulates multistep cell fate transitions with restricted reversibility.PLoS computational biology · 2019Article
- Molecular Mechanisms Controlling Foxp3 Expression in Health and Autoimmunity: From Epigenetic to Post-translational Regulation.Frontiers in immunology · 2019Review
- From Discrete to Continuous Modeling of Lymphocyte Development and Plasticity in Chronic Diseases.Frontiers in immunology · 2019Review
- Understanding the Dynamics of T-Cell Activation in Health and Disease Through the Lens of Computational Modeling.JCO clinical cancer informatics · 2019Review
- Differential T-cell receptor signals for T helper cell programming.Immunology · 2018Review
- mTOR Complex 1 Signaling Regulates the Generation and Function of Central and Effector Foxp3Journal of immunology (Baltimore, Md. : 1950) · 2018Article
- Target Control in Logical Models Using the Domain of Influence of Nodes.Frontiers in physiology · 2018Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Variations in T cell receptor (TCR) signal strength, as indicated by differential activation of downstream signaling pathways, determine the fate of naïve T cells after encounter with antigen. Low-strength signals favor differentiation into regulatory T (T(reg)) cells containing the transcription factor Foxp3, whereas high-strength signals favor generation of interleukin-2-producing T helper (T(H)) cells. We constructed a logic circuit model of TCR signaling pathways, a major feature of which is an incoherent feed-forward loop involving both TCR-dependent activation of Foxp3 and its inhibition by mammalian target of rapamycin (mTOR), leading to the transient appearance of Foxp3(+) cells under T(H) cell-generating conditions. Experiments confirmed this behavior and the prediction that the immunosuppressive cytokine TGF-β (transforming growth factor-β) could generate T(reg) cells even during continued Akt-mTOR signaling. We predicted that sustained mTOR activity could suppress FOXP3 expression upon TGF-β removal, suggesting a possible mechanism for the experimentally observed instability of Foxp3(+) cells. Our model predicted, and experiments confirmed, that transient stimulation of cells with high-dose antigen generated T(H), T(reg), and nonactivated cells in proportions depending on the duration of TCR stimulation. Experimental analysis of cells after antigen removal identified three populations that correlated with these T cell fates. Further analysis of simulations implicated a negative feedback loop involving Foxp3, the phosphatase PTEN, and Akt-mTOR in determining fate. These results suggest that there is a critical time after TCR stimulation during which heterogeneity in the differentiating population of cells leads to increased plasticity of cell fate.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.