Research ArticleImmunology

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

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

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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.

Abstract

Cytokines belonging to the common gamma chain (γc) family depend on the shared γc receptor subunit for signaling. We report the existence of a fast, cytokine-induced pathway cross-talk acting at the receptor level, resulting from a limiting amount of γc on the surface of T cells. We found that this limited abundance of γc reduced interleukin-4 (IL-4) and IL-21 responses after IL-7 preexposure but not vice versa. Computational modeling combined with quantitative experimental assays indicated that the asymmetric cross-talk resulted from the ability of the “private” IL-7 receptor subunits (IL-7Rα) to bind to many of the γc molecules even before stimulation with cytokine. Upon exposure of T cells to IL-7, the high affinity of the IL-7Rα:IL-7 complex for γc further reduced the amount of free γc in a manner dependent on the concentration of IL-7. Measurements of bioluminescence resonance energy transfer (BRET) between IL-4Rα and γc were reduced when IL-7Rα was overexpressed. Furthermore, in a system expressing IL-7Rα, IL-4Rα, and γc, BRET between IL-4Rα and γc increased after IL-4 binding and decreased when cells were preexposed to IL-7, supporting the assumption that IL-7Rα and the IL-7Rα:IL-7 complex limit the accessibility of γc for other cytokine receptor complexes. We propose that in complex inflammatory environments, such asymmetric cross-talk establishes a hierarchy of cytokine responsiveness.

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