Publication date: Available online 20 May 2019
Source: Journal of Allergy and Clinical Immunology
Author(s): Peng Wang, Yana Xu, Jiayu Zhang, Lu Shi, Tong Lei, Yangxiao Hou, Zhongbing Lu, Yong Zhao
Abstract
Graphical abstract
Background
T helper 9 (Th9) cells have emerged as important mediators of allergic airway inflammation. There is evidence that general control nonderepressible 2 (GCN2) affects the immune response under some stress conditions. However, whether GCN2 regulates CD4+ T cell differentiation during allergic inflammation remains unknown.
Objective
To clarify the regulatory roles of GCN2 in CD4+ T cell subset differentiation and its significance in allergic airway inflammation.
Methods
The effects of GCN2 in the differentiation of Th cell subsets were detected using the in vitro induction system. GCN2 knockout (GCN2KO) mice, OVA-induced allergic airway inflammation and adoptive transfer mouse models were used to determine the significance of GCN2 in Th9 differentiation and allergic airway inflammation in vivo. RNA-Seq, real-time PCR, Western blots and other molecular approaches were used to identify the molecular mechanisms relevant to the regulation of GCN2 in Th9 cell differentiation.
Results
GCN2 deficiency significantly inhibited the differentiation of Th9 cells but not Th1, Th2, and Treg cells. GCN2KO mice and recombination activity gene-2 knockout (Rag2KO) mice that received adoptively transferred GCN2-deficient CD4+ T cells exhibited reduced Th9 differentiation and less severe allergic airway inflammation. Furthermore, the isolated GCN2-deficient Th9 cells also mediated less severe allergic airway inflammation upon adoptive transfer. Mechanistically, GCN2 deficiency inhibits Th9 cell differentiation through a hypoxia-inducible factor 1α (HIF1α)-dependent glycolytic pathway.
Conclusion
Our results reveal a novel role of GCN2 in Th9 cell differentiation. Our findings indicate that new strategies to inhibit GCN2 activity may provide novel approaches to attenuate allergic airway inflammation.
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