Paradoxical signaling by a secreted molecule leads to homeostasis of cell levels

Yuval Hart, Shlomit Reich-Zeliger, Yaron E. Antebi, Irina Zaretsky, Avraham E. Mayo, Uri Alon, Nir Friedman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

A widespread feature of extracellular signaling in cell circuits is paradoxical pleiotropy: the same secreted signaling molecule can induce opposite effects in the responding cells. For example, the cytokine IL-2 can promote proliferation and death of T cells. The role of such paradoxical signaling remains unclear. To address this, we studied CD4+ T cell expansion in culture. We found that cells with a 30-fold difference in initial concentrations reached a homeostatic concentration nearly independent of initial cell levels. Below an initial threshold, cell density decayed to extinction (OFF-state). We show that these dynamics relate to the paradoxical effect of IL-2, which increases the proliferation rate cooperatively and the death rate linearly. Mathematical modeling explained the observed cell and cytokine dynamics and predicted conditions that shifted cell fate from homeostasis to the OFF-state. We suggest that paradoxical signaling provides cell circuits with specific dynamical features that are robust to environmental perturbations.

Original languageAmerican English
Pages (from-to)1022-1032
Number of pages11
JournalCell
Volume158
Issue number5
DOIs
StatePublished - 28 Aug 2014
Externally publishedYes

Bibliographical note

Funding Information:
This research was supported by grants from the Israeli Science Foundation, The Human Frontier Science Program, and the European Research Council under the European Union’s 7 th Framework Programme (ERC Grant agreement 249919) (to U.A.). This research was also supported by a grant from the I-CORE Program of the Planning and Budgeting Committee and the Israel Science Foundation (to N.F.). U.A. is the incumbent of the Abisch-Frenkel Professorial Chair. N.F. is the incumbent of the Pauline Recanati Career Development Chair of Immunology. Y.H. wishes to thank Naama Barkai for fruitful discussions.

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