Tuning of cytokine signaling through imbalanced abundances of receptors and kinases

Cells use surface receptors to detect extra-cellular ligands (e.g., growth factors or cytokines) and engender signaling cascades. We explore the effect of cell-to-cell variability in receptor subunit copy number for cells responding to γc cytokines (e.g., IL-2, IL-7 and IL-15). We find that primary T cells expressing higher levels of the common γc receptor chain have weaker responses to IL-7, both in terms of lowered STAT5 phosphorylation amplitude and higher EC 50. A mathematical model that accounts for abundance imbalance (e.g., insufficient expression of JAK kinases compared to the number of receptors, or γc competition for other receptor subunit chains) predicts the formation of non-signalling complexes, consistent with the observed cellular behaviour. This type of built-in limit on signaling responses illustrates how phenotypic heterogeneity generates biological functional diversity