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

Cytokines belonging to the common gamma chain (gamma(c)) family depend on the shared gamma(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 gamma(c) on the surface of T cells. We found that this limited abundance of gamma(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-7R alpha) to bind to many of the gamma(c) molecules even before stimulation with cytokine. Upon exposure of T cells to IL-7, the high affinity of the IL-7R alpha:IL-7 complex for gamma(c) further reduced the amount of free gamma(c) in a manner dependent on the concentration of IL-7. Measurements of bioluminescence resonance energy transfer (BRET) between IL-4R alpha and gamma(c) were reduced when IL-7R alpha was overexpressed. Furthermore, in a system expressing IL-7R alpha, IL-4R alpha, and gamma(c), BRET between IL-4R alpha and gamma(c) increased after IL-4 binding and decreased when cells were preexposed to IL-7, supporting the assumption that IL-7R alpha and the IL-7R alpha:IL-7 complex limit the accessibility of gamma(c) for other cytokine receptor complexes. We propose that in complex inflammatory environments, such asymmetric cross-talk establishes a hierarchy of cytokine responsiveness.