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 γ c 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 γ c 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. Significance Statement Cells rely on cytokines to coordinate their activation, differentiation, proliferation and survival. In particular, γ c cytokines (interleukins IL-2, 4, 7, 9, 15, and 21) regulate the fate of leukocytes. The signaling cascade induced by these cytokines is relatively simple, and involves the phosphorylation of receptor-associated Janus-like kinases (JAK). Here, we explore the cell-to-cell variability of cytokine responses in primary mouse T cells, and find a paradoxical and quantitative imprint of receptor expression levels and other signaling components. For instance, high abundance of the common γ c chain reduces cytokine responses (both in terms of signaling amplitudes and characteristic cytokine concentrations triggering 50% of the response). We develop mathematical models to quantify how limited abundances of signaling components ( e . g ., JAK or other cytokine receptor subunit chains) may explain our experimental observations. We conclude by generalizing this observation of cell-to-cell signaling variability to other ligand-receptor-kinase systems.