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

Cytokines belonging to the common gamma chain (γ c ) family depend on the shared γ c 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 γ c on the surface of T cells. We found that this limited abundance of γ c 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 γ c 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 γ c further reduced the amount of free γ c in a manner dependent on the concentration of IL-7. Measurements of bioluminescence resonance energy transfer (BRET) between IL-4Rα and γ c were reduced when IL-7Rα was overexpressed. Furthermore, in a system expressing IL-7Rα, IL-4Rα, and γ c , BRET between IL-4Rα and γ c 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 γ c for other cytokine receptor complexes. We propose that in complex inflammatory environments, such asymmetric cross-talk establishes a hierarchy of cytokine responsiveness.