title: Paradoxical signaling by a secreted molecule leads to homeostasis of cell levels.
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.
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Hart
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Shlomit
authors.initials: S
authors.lastname: Reich-Zeliger
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Yaron E
authors.initials: YE
authors.lastname: Antebi
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Irina
authors.initials: I
authors.lastname: Zaretsky
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Avraham E
authors.initials: AE
authors.lastname: Mayo
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Uri
authors.initials: U
authors.lastname: Alon
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: nir.friedman@weizmann.ac.il.
authors.forename: Nir
authors.initials: N
authors.lastname: Friedman
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002452:Cell Count; D016923:Cell Death; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006706:Homeostasis; D007376:Interleukin-2 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D007376:Interleukin-2; D019253:Proto-Oncogene Proteins c-bcl-2; C052617:Bcl2 protein, mouse