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上海士鋒生物關(guān)于一種白介素-2 “superkine”的人工合成
點(diǎn)擊次數(shù)：1562 發(fā)布時間：2013-6-20
Chris Garcia及其同事闡明了使得T-細(xì)胞對免疫刺激性細(xì)胞因子白介素-2（IL-2）敏感性增強(qiáng)的分子機(jī)制。他們利用這一信息來人工合成一種“單鏈IL-2 superkine”，它獨(dú)立于其α-受體（IL-2Rα 或 CD25）發(fā)揮功能。這一新的superkine在誘導(dǎo)抗腫瘤T-細(xì)胞反應(yīng)方面比IL-2更有效，而毒副作用更少。
Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine’
The immunostimulatory cytokine interleukin-2 （IL-2） is a growth factor for a wide range of leukocytes, including T cells and natural killer （NK） cells1, 2, 3. Considerable effort has been invested in using IL-2 as a therapeutic agent for a variety of immune disorders ranging from AIDS to cancer. However, adverse effects have limited its use in the clinic. On activated T cells, IL-2 signals through a quaternary ‘high affinity’ receptor complex consisting of IL-2, IL-2Rα （termed CD25）, IL-2Rβ and IL-2Rγ4, 5, 6, 7, 8. Naive T cells express only a low density of IL-2Rβ and IL-2Rγ, and are therefore relatively insensitive to IL-2, but acquire sensitivity after CD25 expression, which captures the cytokine and presents it to IL-2Rβ and IL-2Rγ. Here, using in vitro evolution, we eliminated the functional requirement of IL-2 for CD25 expression by engineering an IL-2 ‘superkine’ （also called super-2） with increased binding affinity for IL-2Rβ. Crystal structures of the IL-2 superkine in free and receptor-bound forms showed that the evolved mutations are principally in the core of the cytokine, and molecular dynamics simulations indicated that the evolved mutations stabilized IL-2, reducing the flexibility of a helix in the IL-2Rβ binding site, into an optimized receptor-binding conformation resembling that when bound to CD25. The evolved mutations in the IL-2 superkine recapitulated the functional role of CD25 by eliciting potent phosphorylation of STAT5 and vigorous proliferation of T cells irrespective of CD25 expression. Compared to IL-2, the IL-2 superkine induced superior expansion of cytotoxic T cells, leading to improved antitumour responses in vivo, and elicited proportionally less expansion of T regulatory cells and reduced pulmonary oedema. Collectively, we show that in vitro evolution has mimicked the functional role of CD25 in enhancing IL-2 potency and regulating target cell specificity, which has implications for immunotherapy.