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

机译：细胞因子受体与常见伽玛链之间的亲和力等级导致途径交谈

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摘要

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.
机译：属于常见的γ链（γ（c））家族的细胞因子依赖于信号传导的共用γ（c）受体亚基。我们报告存在于受体水平的快速，细胞因子诱导的途径交叉谈，由T细胞表面的限制量的γ（c）产生。我们发现，在IL-7预筛后，这种有限的γ-4（IL-4）和IL-21反应减少，但不反之亦然。结合定量实验测定的计算建模表明，即使在用细胞因子刺激之前，“私人”IL-7受体亚单位（IL-7Rα）与许多γ（C）分子结合的不对称串扰也是如此。 。在将T细胞暴露于IL-7时，IL-7Rα的高亲和力：IL-7γ（c）的络合物以取决于IL-7浓度的方式进一步降低了游离γ（c）的量。当IL-7Rα过表达时，减少了IL-4Rα和γ（C）之间的生物发光共振能量转移（BRET）的测量。此外，在表达IL-7Rα，IL-4Rα和γ（c）的系统中，在IL-4结合后IL-4Rα和γ（c）之间的BRET增加，当细胞预先置于IL-7时，支持IL-7Rα和IL-7Rα的假设：IL-7复合物限制其他细胞因子受体复合物的γ（c）的可访问性。我们提出在复杂的炎症环境中，这种不对称的串扰建立了细胞因子响应性的层次结构。

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  • 来源
    《Science Signaling》 |2018年第524期|共12页
  • 作者

    Gonnord Pauline; Angermann Bastian R.; Sadtler Kaitlyn; Gombos Erin; Chappert Pascal; Meier-Schellersheim Martin; Varma Rajat;

  • 作者单位

    NIAID Computat Biol Unit Lab Syst Biol NIH 9000 Rockville Pike Bethesda MD 20892 USA;

    NIAID Computat Biol Unit Lab Syst Biol NIH 9000 Rockville Pike Bethesda MD 20892 USA;

    NIAID Computat Biol Unit Lab Syst Biol NIH 9000 Rockville Pike Bethesda MD 20892 USA;

    NIAID Computat Biol Unit Lab Syst Biol NIH 9000 Rockville Pike Bethesda MD 20892 USA;

    NIAID Computat Biol Unit Lab Syst Biol NIH 9000 Rockville Pike Bethesda MD 20892 USA;

    NIAID Computat Biol Unit Lab Syst Biol NIH 9000 Rockville Pike Bethesda MD 20892 USA;

    NIAID Computat Biol Unit Lab Syst Biol NIH 9000 Rockville Pike Bethesda MD 20892 USA;

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  • 正文语种 eng
  • 中图分类 细胞生物学;
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