Tuning of cytokine signaling through imbalanced abundances of receptors and kinases

Abstract

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{gamma} c cytokines (e.g., IL-2, IL-7 and IL-15). We find that primary T cells expressing higher levels of the common{gamma} c receptor chain have weaker responses to IL-7, both in terms of lowered STAT5 phosphorylation amplitude and higher EC50. A mathematical model that accounts for abundance imbalance (e.g., insufficient expression of JAK kinases compared to the number of receptors, or{gamma} 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 StatementCells rely on cytokines to coordinate their activation, differentiation, proliferation and survival. In particular,{gamma} 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{gamma} 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.