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Bcl6 and Blimp1 reciprocally regulate ST2+ Treg-cell development in the context of allergic airway inflammation.
Journal of Allergy and Clinical Immunology ( IF 11.4 ) Pub Date : 2020-03-13 , DOI: 10.1016/j.jaci.2020.03.002
Byunghee Koh 1 , Benjamin J Ulrich 2 , Andrew S Nelson 3 , Gayathri Panangipalli 4 , Rakshin Kharwadkar 5 , Wenting Wu 6 , Markus M Xie 2 , Yongyao Fu 2 , Matthew J Turner 7 , Sophie Paczesny 1 , Sarath Chandra Janga 4 , Alexander L Dent 2 , Mark H Kaplan 1
Affiliation  

Background

Bcl6 is required for the development of T follicular helper cells and T follicular regulatory (Tfr) cells that regulate germinal center responses. Bcl6 also affects the function of regulatory T (Treg) cells.

Objective

The goal of this study was to define the functions of Bcl6 in Treg cells, including Tfr cells, in the context of allergic airway inflammation.

Methods

We used a model of house dust mite sensitization to challenge wild-type, Bcl6fl/fl Foxp3-Cre, and Prdm1 (Blimp1)fl/fl Foxp3-Cre mice to study the reciprocal roles of Bcl6 and Blimp1 in allergic airway inflammation.

Results

In the house dust mite model, Tfr cells repress the production of IgE and Bcl6+ Treg cells suppress the generation of type 2 cytokine–producing cells in the lungs. In mice with Bcl6-deficient Treg cells, twice as many ST2+ (IL-33R+) Treg cells develop as are observed in wild-type mice. ST2+ Treg cells in the context of allergic airway inflammation are Blimp1 dependent, express type 2 cytokines, and share features of visceral adipose tissue Treg cells. Bcl6-deficient Treg cells are more susceptible, and Blimp1-deficient Treg cells are resistant, to acquiring the ST2+ Treg–cell phenotype in vitro and in vivo in response to IL-33. Bcl6-deficient ST2+ Treg cells, but not Bcl6-deficient ST2+ conventional T cells, strongly promote allergic airway inflammation when transferred into recipient mice. Lastly, ST2 is required for the exacerbated allergic airway inflammation in Bcl6fl/fl Foxp3-Cre mice.

Conclusions

During allergic airway inflammation, Bcl6 and Blimp1 play dual roles in regulating Tfr-cell activity in the germinal center and in the development of ST2+ Treg cells that promote type 2 cytokine responses.



中文翻译:

Bcl6 和 Blimp1 在过敏性气道炎症的背景下相互调节 ST2+ Treg 细胞的发育。

背景

Bcl6 是调节生发中心反应的 T 滤泡辅助细胞和 T 滤泡调节 (Tfr) 细胞的发育所必需的。Bcl6 还影响调节性 T (Treg) 细胞的功能。

客观的

本研究的目的是在过敏性气道炎症的背景下确定 Bcl6 在 Treg 细胞(包括 Tfr 细胞)中的功能。

方法

我们使用屋尘螨过敏的模式来挑战野生型,Bcl6转录FL / FL Foxp3的Cre重组酶,和PRDM1(BLIMP1)FL / FL Foxp3的Cre重组酶的小鼠研究Bcl6转录因子和BLIMP1的过敏性气道炎症的倒数角色。

结果

在屋尘螨模型中,Tfr 细胞抑制 IgE 的产生,Bcl6 + Treg 细胞抑制肺中 2 型细胞因子产生细胞的产生。在具有 Bcl6 缺陷型 Treg 细胞的小鼠中,产生的 ST2 + (IL-33R + ) Treg 细胞是在野生型小鼠中观察到的两倍。过敏性气道炎症背景下的ST2 + Treg 细胞依赖于 Blimp1,表达 2 型细胞因子,并具有内脏脂肪组织 Treg 细胞的特征。Bcl6 缺陷型 Treg 细胞更易感,Blimp1 缺陷型 Treg 细胞对在体外体内响应 IL-33获得 ST2 + Treg 细胞表型具有抗性。Bcl6 缺陷型 ST2+ Treg 细胞,但不是 Bcl6 缺陷的 ST2 +常规 T 细胞,当转移到受体小鼠时,强烈促进过敏性气道炎症。最后,Bcl6 fl/fl Foxp3-Cre 小鼠过敏性气道炎症加剧需要 ST2 。

结论

在过敏性气道炎症期间,Bcl6 和 Blimp1 在调节生发中心的 Tfr 细胞活性和促进 2 型细胞因子反应的 ST2 + Treg 细胞的发育中发挥双重作用。

更新日期:2020-03-13
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