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Engineered interleukin-2 antagonists for the inhibition of regulatory T cells.

机译:工程白介素2拮抗剂,用于抑制调节性T细胞。

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The immunosuppressive effects of CD4+ CD25 high regulatory T cells (Tregs) interfere with antitumor immune responses in cancer patients. Here, we present a novel class of engineered human interleukin (IL)-2 analogs that antagonizes the IL-2 receptor, for inhibiting regulatory T cell suppression. These antagonists have been engineered for high affinity to the alpha subunit of the IL-2 receptor and very low affinity to either the beta or gamma subunit, resulting in a signaling-deficient IL-2 analog that sequesters the IL-2 receptor alpha subunit from wild type IL-2. Two variants, "V91R" and "Q126T" with residue substitutions that disrupt the beta and gamma subunit binding interfaces, respectively, have been characterized in both a T cell line and in human primary Tregs. These mutants retain their high affinity binding to IL-2 receptor alpha subunit, but do not activate STAT5 phosphorylation or stimulate T cell growth. The 2 mutants competitively antagonize wild-type IL-2 signaling through the IL-2 receptor with similar efficacy, with inhibition constants of 183 pM for V91R and 216 pM for Q126T. Here, we present a novel approach to CD25-mediated Treg inhibition, with the use of an engineered human IL-2 analog that antagonizes the IL-2 receptor.
机译:CD4 + CD25高调节性T细胞(Tregs)的免疫抑制作用会干扰癌症患者的抗肿瘤免疫反应。在这里,我们介绍了一类新型的工程化人白介素(IL)-2类似物,该类拮抗IL-2受体的抑制性T细胞抑制作用。对这些拮抗剂进行了改造,使其对IL-2受体的α亚基具有高亲和力,而对β或γ亚基的亲和力却非常低,从而导致信号不足的IL-2类似物与IL-2受体的α亚基隔离野生型IL-2。已经在T细胞系和人原代Tregs中表征了两个变体,分别具有破坏β和γ亚基结合界面的残基取代的“ V91R”和“ Q126T”。这些突变体保留了它们与IL-2受体α亚基的高亲和力结合,但不激活STAT5磷酸化或刺激T细胞生长。 2个突变体以相似的功效竞争性拮抗通过IL-2受体的野生型IL-2信号传导,V91R的抑制常数为183 pM,Q126T的抑制常数为216 pM。在这里,我们提出了一种新型的CD25介导的Treg抑制方法,该方法使用的是工程化的人IL-2类似物,可拮抗IL-2受体。

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