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

Research output: Contribution to journalArticlepeer-review


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 languageEnglish
Pages (from-to)1022-1032
Number of pages11
Issue number5
StatePublished - 28 Aug 2014

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)


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