Tuning of cytokine signaling through imbalanced abundances of receptors and kinases

Abstract

Cells rely on cytokines to coordinate their activation, differentiation, proliferation and survival. In particular, γC 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.

Influence of Canonical and Non-Canonical IFNLR1 Isoform Expression on Interferon Lambda Signaling

“…It has been shown that overexpression of cell surface receptors can decrease the cellular response to their cognate biological stimuli [ 45 ], and that overexpression of a receptor subunit without concordant overexpression of downstream signaling molecules can lead to the formation of receptor complexes capable of binding ligands but unable to transduce signals [ 46 ]. As FLAG-Iso1 overexpression augmented the IFNL3 response, regardless of dox-induction, we find it less likely that FLAG-Iso2 overexpression diminished cell sensitivity to IFNL3 by titrating necessary signaling components.…”