Diverse continuum of CD4⁺ T-cell states is determined by hierarchical additive integration of cytokine signals

During cell differentiation, progenitor cells integrate signals from their environment that guide their development into specialized phenotypes. The ways by which cells respond to complex signal combinations remain difficult to analyze and model. To gain additional insight into signal integration, w...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 114; no. 31; pp. E6447 - E6456
Main Authors Eizenberg-Magar, Inbal, Rimer, Jacob, Zaretsky, Irina, Lara-Astiaso, David, Reich-Zeliger, Shlomit, Friedman, Nir
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 01.08.2017
SeriesPNAS Plus
Subjects
Biological Sciences
PNAS Plus
mathematical modeling
cell differentiation
T cells
CD4 T-cell lineages
systems immunology
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Summary:During cell differentiation, progenitor cells integrate signals from their environment that guide their development into specialized phenotypes. The ways by which cells respond to complex signal combinations remain difficult to analyze and model. To gain additional insight into signal integration, we systematically mapped the response of CD4⁺ T cells to a large number of input cytokine combinations that drive their differentiation. We find that, in response to varied input combinations, cells differentiate into a continuum of cell fates as opposed to a limited number of discrete phenotypes. Input cytokines hierarchically influence the cell population, with TGFβ being most dominant followed by IL-6 and IL-4. Mathematical modeling explains these results using additive signal integration within hierarchical groups of input cytokine combinations and correctly predicts cell population response to new input conditions. These findings suggest that complex cellular responses can be effectively described using a segmented linear approach, providing a framework for prediction of cellular responses to new cytokine combinations and doses, with implications to fine-tuned immunotherapies.
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Edited by Federica Sallusto, Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland, and accepted by Editorial Board Member Tadatsugu Taniguchi June 2, 2017 (received for review September 28, 2016)
1I.E.-M. and J.R. contributed equally to this work.
Author contributions: I.E.-M., J.R., and N.F. designed research; I.E.-M., J.R., I.Z., D.L.-A., and S.R.-Z. performed research; I.E.-M., J.R., and N.F. analyzed data; and I.E.-M., J.R., and N.F. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1615590114