Engineered interleukin-2 antagonists for the inhibition of regulatory T cells.
Engineered interleukin-2 antagonists for the inhibition of regulatory T cells.
复制标题
DOI：
10.1097/cji.0b013e3181b528da
复制
发表时间：
2009-11
期刊：
影响因子：
--
通讯作者：
Wittrup KD
中科院分区：
文献类型：
--
作者：
Liu DV;Maier LM;Hafler DA;Wittrup KD
CD4+ cd25高调节性T细胞的免疫抑制作用干扰癌症患者的抗肿瘤免疫反应。在这里，我们提出了一类新的工程人类白细胞介素(IL)-2类似物，拮抗IL-2受体，抑制调节性T细胞抑制。这些拮抗剂对IL-2受体的α亚基具有高亲和力，而对β或γ亚基的亲和力非常低，导致信号缺陷的IL-2类似物将IL-2受体α亚基与野生型IL-2隔离开来。两个变体，“V91R”和“Q126T”，分别具有残基取代，破坏β和γ亚基结合界面，已经在T细胞系和人类初级调节性T细胞中被表征。这些突变体保留了与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。两种突变体通过IL-2受体竞争性拮抗野生型IL-2信号，效果相似，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cd25介导的Treg抑制的新方法，使用工程化的人IL-2类似物来拮抗IL-2受体。
The immunosuppressive effects of CD4+ CD25high regulatory T cells interfere with anti-tumor immune responses in cancer patients. Here, we present a novel class of engineered human Interleukin (IL)-2 analogues that antagonize the IL-2 receptor, for inhibiting regulatory T cell suppression. These antagonists have been engineered for high affinity to the α subunit of the IL-2 receptor and very low affinity to either the β or γ subunit, resulting in a signaling-deficient IL-2 analogue that sequesters the IL-2 receptor α subunit from wild type IL-2. Two variants, “V91R” and “Q126T” with residue substitutions that disrupt the β and γ subunit binding interfaces, respectively, have been characterized in both a T cell line and in human primary regulatory T cells. These mutants retain their high affinity binding to IL-2 receptor α subunit, but do not activate STAT5 phosphorylation or stimulate T cell growth. The two 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 analogue that antagonizes the IL-2 receptor.