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A Common Druggable Defect in Regulatory T Cells from Patients with Autoimmunity
Critical Reviews in Immunology ( IF 1.3 ) Pub Date : 2020-01-01 , DOI: 10.1615/critrevimmunol.2020034631
Luis Soares 1 , Linda Yip 1 , Clarence R Hurt 2 , Garrison Fathman 3
Affiliation  

We identified a druggable defect in IL-2 receptor (IL-2R) signaling by comparing the response of regulatory T cells (Tregs) of autoimmune disease patients to that of healthy controls. This defect was in the inhibition of Treg desensitization and was shared across various autoimmune diseases. Low-dose IL-2 stimulation results in maintained pSTAT5 expression for > 4 h, allowing the Treg transcriptome for "function" to be transcribed. Tregs of autoimmune Tregs of autoimmune disease patients more rapidly terminate IL-2R signaling through STAT5. Prolonged pSTAT5 expression following IL-2R activation is mediated by blocking proteasomal degradation of pJAKl, which is associated with the IL-2RP chain. In Tregs of controls, this is accomplished by inhibiting a requisite-activating post-translational modification (neddylation) of the SOCS3/Cul5 cullin ring ligase (CRL), which normally ubiquitinates pJAKl. Many receptor-associated tyrosine kinases are desensitized by a CRL. Tregs uniquely constitutively express an E3 ligase known as the gene related to anergy in lymphocytes (GRAIL), which ubiquinates the exact lysine on the Cul5 protein that needs to be neddylated as a condition for the activation and consequent ubiquitination of pJAKl. There is a defect in this GRAIL-associated pathway of competitive inhibition of neddylation in the Tregs of autoimmune disease patients. This defect can be mitigated by the application of a small-molecule drug known as a neddylation activating enzyme inhibitor (NAEi). Low-dose IL-2 and an NAEi as a protein-drug conjugate was found to be much more effective than simply using low-dose IL-2 or a combination of low-dose IL-2 and an NAEi systemically in treating animal models of autoimmune diseases.

中文翻译:

自身免疫性患者调节性T细胞常见的药物缺陷

我们通过比较自身免疫性疾病患者的调节性T细胞(Tregs)与健康对照的应答,在IL-2受体(IL-2R)信号传导中发现了可治疗的缺陷。该缺陷在于对Treg脱敏的抑制,并且在各种自身免疫疾病中共有。低剂量的IL-2刺激可导致pSTAT5表达维持> 4小时,从而转录“功能”的Treg转录组。自身免疫性疾病的Treg自身免疫性疾病患者的Treg通过STAT5更快地终止IL-2R信号传导。IL-2R激活后延长的pSTAT5表达是通过阻断pJAK1的蛋白酶体降解来介导的,该降解与IL-2RP链有关。在控件的Treg中 这是通过抑制通常会泛素化pJAK1的SOCS3 / Cul5 cullin环连接酶(CRL)的必要激活的翻译后修饰(内酰胺化)来实现的。许多受体相关的酪氨酸激酶被CRL脱敏。Tregs独特地组成性地表达一种称为E3的E3连接酶。与淋巴细胞无反应相关的基因(GRAIL),其泛素化Cul5蛋白上的确切赖氨酸,需要将其进行二氨基化,作为pJAK1激活和随后泛素化的条件。在自身免疫性疾病患者的Treg中,这种与GRAIL相关的竞争抑制腺苷酸化的途径存在缺陷。这种缺陷可以通过应用一种称为小肽活化酶抑制剂(NAEi)的小分子药物来缓解。发现低剂量IL-2和NAEi作为蛋白质-药物偶联物比单纯使用低剂量IL-2或低剂量IL-2和NAEi的组合更有效地治疗动物模型自身免疫性疾病。
更新日期:2020-01-01
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