Genetics and Pathogenesis of Allergy Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
Office of Biotechnology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Md.
J Allergy Clin Immunol. 2019 Mar;143(3):1108-1118.e4. doi: 10.1016/j.jaci.2018.06.036. Epub 2018 Jul 18.
Patients with loss-of-function (LOF) signal transducer and activator of transcription 3 (STAT3) mutations have dermatitis, enhanced IgE production despite a relative lack of immediate hypersensitivity, recurrent infection, and an increased rate of lymphoma in addition to a number of skeletal and connective tissue abnormalities. Patients with STAT1 gain-of-function (GOF) mutations also have susceptibility to candidiasis and sinopulmonary infection, as well as autoimmunity and squamous cell carcinoma, in addition to even more broad phenotypes.
Because of the link between T9 cells and allergic inflammation, autoimmunity, and antitumor surveillance and because evidence shows a role for either STAT3 or STAT1 in T9 differentiation conflicts, we sought to determine the status on this lineage of STAT1 GOF and STAT3 LOF mutations in human subjects.
We detected IL-9 levels and T9 differentiation in patients with STAT3 LOF and STAT1 GOF mutations, together with T9 transcript factors, and partially rescued their deficiency in vitro by adding cytokines they lacked or transfecting key molecules.
We found that PBMCs or sorted naive CD4 T cells from patients with STAT3 LOF and STAT1 GOF mutations had impaired T9 generation/differentiation. STAT3 inhibition in normal T9 cultures diminished early IL-21 induction and late IL-9 production, whereas exogenous IL-21 enhanced T9 differentiation, even with STAT3 inhibition, by restoring suppressor of cytokine signaling 3 expression and thus inhibiting excessive phosphorylated signal transducer and activator of transcription (p-STAT) 1 activation. Furthermore, exogenous expression of suppressor of cytokine signaling 3 or either T-bet or STAT1 RNA interference in STAT3 LOF cells partially rescued IL-9 differentiation.
Collectively, these results suggest that human T9 differentiation depends on normal p-STAT3 and IL-21 production to suppress p-STAT1 activation and T-bet transcription.
具有信号转导子和转录激活子 3（STAT3）功能丧失（LOF）突变的患者有皮炎，尽管存在相对缺乏即刻过敏反应，但 IgE 产生增强，复发性感染，以及增加淋巴瘤的发生率，此外还有许多骨骼和结缔组织异常。具有 STAT1 获得性功能（GOF）突变的患者也易患念珠菌病和鼻肺感染，以及自身免疫和鳞状细胞癌，此外还有更广泛的表型。
由于 T9 细胞与过敏炎症、自身免疫和抗肿瘤监视之间存在联系，并且证据表明 STAT3 或 STAT1 在 T9 分化中具有作用，因此我们试图确定人类中 STAT1 GOF 和 STAT3 LOF 突变在该谱系中的状态。
我们检测了 STAT3 LOF 和 STAT1 GOF 突变患者的 IL-9 水平和 T9 分化，以及 T9 转录因子，并通过添加它们缺乏的细胞因子或转染关键分子，在体外部分挽救了它们的缺陷。
我们发现 STAT3 LOF 和 STAT1 GOF 突变患者的 PBMC 或分选的幼稚 CD4 T 细胞的 T9 生成/分化受损。在正常的 T9 培养物中抑制 STAT3 会减少早期的 IL-21 诱导和晚期的 IL-9 产生，而外源性的 IL-21 增强了 T9 分化，即使在抑制 STAT3 的情况下，也通过恢复细胞因子信号转导抑制因子 3 的表达并因此抑制过度磷酸化的信号转导和转录激活子（p-STAT）1 的激活。此外，在 STAT3 LOF 细胞中过表达细胞因子信号转导抑制因子 3 或 T-bet 或 STAT1 RNA 干扰部分挽救了 IL-9 分化。
总的来说，这些结果表明人类 T9 分化依赖于正常的 p-STAT3 和 IL-21 产生来抑制 p-STAT1 激活和 T-bet 转录。
