title: An animated landscape representation of CD4+ T-cell differentiation, variability, and plasticity: insights into the behavior of populations versus cells.
abstract: 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.
authors.affiliation: David H. Smith Center for Vaccine Biology and Immunology, University of Rochester Medical School, Rochester, NY, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Rebhahn
authors.forename: Nan
authors.initials: N
authors.lastname: Deng
authors.forename: Gaurav
authors.initials: G
authors.lastname: Sharma
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Livingstone
authors.forename: Sui
authors.initials: S
authors.lastname: Huang
authors.forename: Tim R
authors.initials: TR
authors.lastname: Mosmann
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D010641:Phenotype
keywords: CD4+ T cells; Cell differentiation; Cytokines; Modeling