Editors' ChoiceCytokine Signaling

New connections: Cytokines learn to share

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Sci. Signal.  03 Apr 2018:
Vol. 11, Issue 524, eaat7446
DOI: 10.1126/scisignal.aat7446

Computational modeling provides insights into the consequences for T cells of having a shared receptor subunit for different cytokines.

The common gamma chain (γc) family of cytokines, which includes interleukin-2 (IL-2), IL-4, IL-7, and IL-21, signal through the heterodimerization of so-called “private” receptor subunits (α chains) with a shared γc receptor subunit. Given that T cells may encounter different combinations of γc cytokines in vivo and because these cytokines induce different functional responses, understanding how differences in the abundances of signaling regulators affect the cellular outcome is important. In the Archives, Cotari et al. used a combination of experimental and computational techniques called cell-to-cell variability analysis (CCVA) to investigate the effects of IL-2Rα on mouse T cell responses to other γc cytokines. They showed that increased IL-2Rα abundance reduced the responsiveness of cells to IL-7 or IL-15. The authors then modeled the formation of receptor signaling complexes on biophysical measurements. These data suggested that IL-2Rα depletes γc by forming functional IL-2R complexes. In this issue of Science Signaling, Gonnord et al. furthered this analysis of signaling cross-talk through their computational modeling and experimental analysis of γc cytokine receptor signaling in naïve T cells. Whereas pretreatment of cells with IL-7 reduced their responsiveness to subsequent exposure to IL-4 or IL-21, pretreatment of cells with either IL-4 or IL-21 had no effect on subsequent treatment with IL-7. Even in unstimulated cells, the γc subunit was preassociated with IL-7Rα and it had greater affinity for IL-7Rα than for IL-4Rα or IL-21Rα. In response to IL-7, the IL-7Rα:γc interaction was enhanced, thus sequestering the γc subunit from the other receptors. Together, these data suggest that the responses of naïve T cells to γc cytokines are hierarchical, which may ensure that certain functional responses are prioritized in a mixed cytokine environment.

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