Malat1通过控制女性Th2细胞的早期分化和对IL-2的反应来调节细胞因子的表达。

IF 3.4 3区 医学 Q2 IMMUNOLOGY
Mags Gwynne, Katie A West, Stijn van Dongen, Ioannis Kourtzelis, Dawn Coverley, Sarah A Teichmann, Kylie R James, James P Hewitson, Dimitris Lagos
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引用次数: 0

摘要

确定免疫两性异形的细胞内在调节因子对治疗多种免疫病理至关重要。我们发现Malat1是女性而不是男性T辅助2 (Th2)细胞中适当的细胞因子表达所必需的。Malat1缺乏会损害雌性小鼠naïve CD4+ T细胞的体外Th2分化,其特征是转录组全效应和细胞因子表达抑制,特别是白细胞介素(IL)-10。在IL-10受体(IL10R)阻断后,IL-4和IL-13也有明显的影响。从机制上讲,Malat1-/-雌性小鼠的naïve CD4+ T细胞表现出早期激活动力学改变和早期分化基因表达受损,包括干扰素刺激基因(ISG)模块的上调。随后抑制IL2Rα和IL2Rγ表达和il -2介导的分化。通过干扰素β处理维持WT细胞早期ISG表达来模拟Malat1缺失的影响,部分地显示了Malat1缺失的影响。在男性细胞中也观察到Malat1缺失对女性细胞的一部分影响。然而,这并不影响终末Th2分化。与女性细胞相比,男性CD4+ T细胞表现出更强的早期活化,在早期分化过程中更高的ISG表达,独立于Malat1维持IL2Rα表达,在晚期分化过程中对外源IL-2的敏感性较低。在体内,雌性(而非雄性)Malat1-/-小鼠表现出Th2细胞因子表达的改变,其特征是在曼氏血吸虫卵(肺2型炎症模型)引发和攻击后,肺和脾脏中IL-10+ Th2细胞的减少。总之,这些发现表明Malat1是免疫两性二态性的一个新的决定因素。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Malat1 regulates female Th2 cell cytokine expression through controlling early differentiation and response to IL-2.

Identifying cell intrinsic regulators of immune sexual dimorphism is critical for treatment of several immunopathologies. We show that Malat1 is required for appropriate cytokine expression in female but not male T helper 2 (Th2) cells. Malat1 deficiency impairs in vitro Th2 differentiation of naïve CD4+ T cells from female mice, characterized by transcriptome-wide effects and suppression of cytokine expression, particularly interleukin (IL)-10. Upon IL-10 receptor (IL10R) blockade a pronounced effect is also seen on IL-4 and IL-13. Mechanistically, naïve CD4+ T cells from Malat1-/- female mice demonstrate altered early activation kinetics and impaired early differentiation gene expression, including upregulation of an interferon-stimulated gene (ISG) module. This is followed by suppression of IL2Rα and IL2Rγ expression and IL-2-mediated differentiation. Mimicking the effect of Malat1 loss by maintaining early ISG expression in WT cells with interferon β treatment partially phenocopies the effects of Malat1 deficiency. A subset of the effects of Malat1 loss in female cells is also observed in male cells. However, this does not affect endpoint Th2 differentiation. Male CD4+ T cells demonstrate stronger early activation, higher ISG expression during early differentiation, maintenance of IL2Rα expression independently of Malat1, and lower sensitivity to exogenous IL-2 during late differentiation compared with female cells. In vivo, female, but not male, Malat1-/- mice demonstrate altered Th2 cytokine expression characterized by a reduction in IL-10+ Th2 cells in both lung and spleen following priming and challenge with Schistosoma mansoni eggs, a model of lung type 2 inflammation. Overall, these findings reveal Malat1 as a novel determinant of immune sexual dimorphism.

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来源期刊
Journal of immunology
Journal of immunology 医学-免疫学
CiteScore
8.20
自引率
2.30%
发文量
495
审稿时长
1 months
期刊介绍: The JI publishes novel, peer-reviewed findings in all areas of experimental immunology, including innate and adaptive immunity, inflammation, host defense, clinical immunology, autoimmunity and more. Special sections include Cutting Edge articles, Brief Reviews and Pillars of Immunology. The JI is published by The American Association of Immunologists (AAI)
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