THE INTERLEUKIN-2 RECEPTOR (IL-2R) - THE IL-2R ALPHA SUBUNIT ALTERS THE FUNCTION OF THE IL-2R BETA SUBUNIT TO ENHANCE IL-2 BINDING AND SIGNALING BY MECHANISMS THAT DO NOT REQUIRE BINDING OF IL-2 TO IL-2R ALPHA SUBUNIT
THE INTERLEUKIN-2 RECEPTOR (IL-2R) - THE IL-2R ALPHA SUBUNIT ALTERS THE FUNCTION OF THE IL-2R BETA SUBUNIT TO ENHANCE IL-2 BINDING AND SIGNALING BY MECHANISMS THAT DO NOT REQUIRE BINDING OF IL-2 TO IL-2R ALPHA SUBUNIT
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DOI：
10.1073/pnas.89.6.2165
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发表时间：
1992-03-15
影响因子：
11.1
通讯作者：
WALDMANN, TA
中科院分区：
文献类型：
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作者：
GRANT, AJ;ROESSLER, E;WALDMANN, TA
白细胞介素 2 (IL-2) 通过其高亲和力受体介导的信号传导涉及 IL-2 和两条 IL-2 结合链（IL-2R-α 和 β 链）之间复杂的相互关系。以前使用可用的试剂很难定义这两个涉及 IL-2 结合和信号转导的 IL-2R 亚基之间的功能相互作用。为了扩展我们对两个结合亚基之间相互作用的理解，我们使用单克隆抗体 HIEI 进行了研究，它干扰 IL-2R-α 和 β 链（分别为 IL-2R-α 和 IL-2R-β）的相互作用。此外，我们使用了两种形式的 IL-2，即重组天然 IL-2 和 F42A，F42A 是一种仅与 IL-2R-β 结合的 IL-2 类似物（Phe-42 --> Ala 取代）。类似物 F42A 表现出野生型 IL-2 的 75-100% 的生物活性。这一观察结果与 Saito 及其同事先前提出的严格分层 IL-2 结合亲和力转换模型不一致 [Saito Y.、Sabe, H.、Suzuki, N.、Kondo, S.、Ogura, T.、Shimizu, A. & Honjo, T. (1988) J. Exp.。医学。 168, 1563-1572]预测了事件的有序序列，其中 IL-2 在与 IL-2R-β 相互作用之前必须首先与 IL-2R-α 结合。先前使用IL-2变体的研究被解释为表明IL-2R-α仅起到将IL-2浓缩到细胞表面的作用，并且IL-2R-α和IL-2R-β之间没有发生其他有意义的相互作用。然而，我们的数据与这一观点不一致。我们根据我们的观察得出这一结论，即抗体 HIEI 与 IL-2R-α 的表位反应并干扰该链与 IL-2R-β 的相互作用，抑制类似物 F42A 介导的 IL-2 依赖性增殖作用。此外，通过阻断IL-2R-α和IL-2R-β与抗体HIEI的相互作用，观察到放射性标记的类似物F42A对IL-2R-β的亲和力降低。在我们提出的模型中，IL-2R-α 通过高亲和力 IL-2R 对 IL-2 介导的信号传导发挥多种功能。这些功能包括质膜二维表面内 IL-2 的浓度以及 IL-2R-β 功能能力的改变，这种作用不需要 IL-2 预先与 IL-2R-α 结合。 IL-2R-α介导的IL-2R-β功能增强涉及IL-2R-β的亲和力转换，增加其对IL-2的亲和力，并且可能涉及IL-2与该IL-2R-β结合后IL-2介导的信号传导的促进。
Interleukin 2 (IL-2)-mediated signaling through its high-affinity receptor involves a complex interrelationship between IL-2 and two IL-2-binding chains, IL-2R-alpha and beta-chains. Previously with the reagents available it was difficult to define functional interactions between these two IL-2R subunits involved in IL-2 binding and signal transduction. To extend our understanding of the interplay between the two binding subunits we have done studies with the monoclonal antibody HIEI, which interferes with interaction of IL-2R-alpha and beta-chains (IL-2R-alpha and IL-2R-beta, respectively). Furthermore, we used two forms of IL-2, recombinant native IL-2 and F42A, an IL-2 analog (Phe-42 --> Ala substitution) that binds only to IL-2R-beta. Analog F42A manifested 75-100% of the bioactivity of wild-type IL-2. This observation is inconsistent with the strict hierarchical IL-2-binding affinity conversion model previously proposed by Saito and coworkers [Saito Y., Sabe, H., Suzuki, N., Kondo, S., Ogura, T., Shimizu, A. & Honjo, T. (1988) J. Exp. Med. 168, 1563-1572] that predicted an ordered sequence of events in which IL-2 must first bind to IL-2R-alpha before its interaction with IL-2R-beta. Previous investigations using IL-2 variants were interpreted to show that IL-2R-alpha merely acts to concentrate IL-2 to the cell surface and that no other meaningful interaction occurred between IL-2R-alpha and IL-2R-beta. However, our data are inconsistent with this view. We draw this conclusion on the basis of our observation that antibody HIEI, which reacts with an epitope of IL-2R-alpha and interferes with interaction of this chain and IL-2R-beta, inhibits the IL-2-dependent proliferative effects mediated by analog F42A. Furthermore, by blocking interaction of IL-2R-alpha and IL-2R-beta with the antibody HIEI, a decrease in the affinity of radiolabeled analog F42A for IL-2R-beta was seen. In our proposed model IL-2R-alpha contributes several functions to IL-2-mediated signaling through the high-affinity IL-2R. These functions include concentration of IL-2 within the two-dimensional surface of the plasma membrane as well as alteration of the functional capacity of IL-2R-beta, an effect that does not require prior binding of IL-2 to IL-2R-alpha. The IL-2R-alpha-mediated augmentation of IL-2R-beta functions involves affinity conversion of IL-2R-beta, increasing its affinity for IL-2, and may involve facilitation of IL-2-mediated signaling after binding of IL-2 to this IL-2R-beta.