Research ArticleImmunology

A hierarchy of affinities between cytokine receptors and the common gamma chain leads to pathway cross-talk

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Science Signaling  03 Apr 2018:
Vol. 11, Issue 524, eaal1253
DOI: 10.1126/scisignal.aal1253

Hierarchical sharing of the γc subunit

Cytokines that belong to the common gamma chain (γc) family, including interleukin-4 (IL-4), IL-7, and IL-21, not only bind to distinct receptor subunits but also rely on a shared γc subunit for signaling. Given the roles of these cytokines in immune cell survival, proliferation, and function, it is important to understand how their shared use of the γc receptor affects the responses of cells to multiple family members. Through computational modeling and experimental analysis of cytokine receptor signaling on naïve T cells, Gonnord et al. showed that whereas treatment with IL-7 reduced the responses of cells to subsequent treatment with IL-4 or IL-21, the reverse was not true. The amount of available γc subunit was limiting and bound more readily to the IL-7 receptor α subunit (IL-7Rα) than to IL-4Rα or IL-21Rα, thus sequestering the γc subunit. The γc subunit preassociated with the IL-7Rα in the absence of cytokine. These data suggest that there exists a hierarchy of responses of naïve T cells to cytokines, which has relevance for cells in inflammatory environments exposed to multiple cytokines.