An animated landscape representation of CD4+ T-cell differentiation, variability, and plasticity: Insights into the behavior of populations versus cells

Recent advances in understanding CD4+ T‐cell differentiation suggest that previous models of a few distinct, stable effector phenotypes were too simplistic. Although several well‐characterized phenotypes are still recognized, some states display plasticity, and intermediate phenotypes exist. As a framework for reexamining these concepts, we use Waddington's landscape paradigm, augmented with explicit consideration of stochastic variations. Our animation program “LAVA” visualizes T‐cell differentiation as cells moving across a landscape of hills and valleys, leading to attractor basins representing stable or semistable differentiation states. The model illustrates several principles, including: (i) cell populations may behave more predictably than individual cells; (ii) analogous to reticulate evolution, differentiation may proceed through a network of interconnected states, rather than a single well‐defined pathway; (iii) relatively minor changes in the barriers between attractor basins can change the stability or plasticity of a population; (iv) intrapopulation variability of gene expression may be an important regulator of differentiation, rather than inconsequential noise; (v) the behavior of some populations may be defined mainly by the behavior of outlier cells. While not a quantitative representation of actual differentiation, our model is intended to provoke discussion of T‐cell differentiation pathways, particularly highlighting a probabilistic view of transitions between states.

• Publication year

  2014

• Venue

  European Journal of Immunology

• Publication date

  2014-08-01

• Fields of study

  Biology, Medicine, Computer Science

• Identifiers
  DOI 10.1002/eji.201444645PMID 24945794PMCID 4209377
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Pillars Article: Control of Regulatory T Cell Development by the Transcription Factor Foxp3. Science 2003. 299: 1057-1061.

  2017cited by this paper
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  2014cited by this paper
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  2014cited by this paper
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  2014cited by this paper
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  2014cited by this paper
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  2014cited by this paper
• The strategy of the genes : a discussion of some aspects of theoretical biology

  2014influential reference
• T helper cells plasticity in inflammation

  2014cited by this paper
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  2013cited by this paper
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  2013cited by this paper
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  2013cited by this paper
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  2013cited by this paper
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  2013cited by this paper
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  2013cited by this paper
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  2013cited by this paper
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  2013cited by this paper
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  2013cited by this paper
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  2013cited by this paper
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  2013cited by this paper
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  2013cited by this paper
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  2013cited by this paper
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  2013cited by this paper
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  2013cited by this paper
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  2013cited by this paper
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  2013cited by this paper
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  2013cited by this paper
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  2012cited by this paper
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  2012cited by this paper
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  2012cited by this paper
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  2012influential reference
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  2012cited by this paper
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  2012cited by this paper
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  2012cited by this paper
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  2011cited by this paper
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  2011cited by this paper
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  2011cited by this paper
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  2011cited by this paper
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  2010cited by this paper
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  2009cited by this paper
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  2009cited by this paper
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  2009cited by this paper
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  2009cited by this paper
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  2009cited by this paper
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  2009cited by this paper
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  2009cited by this paper
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  2009cited by this paper
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  2008cited by this paper
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  2008cited by this paper
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  2008cited by this paper
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  2008cited by this paper
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  2007cited by this paper
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  2007cited by this paper
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  2007cited by this paper
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  2006cited by this paper
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  2006cited by this paper
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  2006cited by this paper
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  2005cited by this paper
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  2005cited by this paper
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  2005cited by this paper
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  2004cited by this paper
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  2004cited by this paper
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  2001cited by this paper
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  2000cited by this paper
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  1999cited by this paper
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  1999cited by this paper
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  1998cited by this paper

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  2019cites this paper
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  2019cites this paper
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  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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  2017cites this paper
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  2017cites this paper
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  2016cites this paper
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  2016cites this paper
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  2016cites this paper
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  2016cites this paper
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  2015cites this paper
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  2015cites this paper
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  2015cites this paper
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