| First Author | Wang P | Year | 2019 |
| Journal | J Allergy Clin Immunol | Volume | 144 |
| Issue | 4 | Pages | 1091-1105 |
| PubMed ID | 31121187 | Mgi Jnum | J:295489 |
| Mgi Id | MGI:6453874 | Doi | 10.1016/j.jaci.2019.04.028 |
| Citation | Wang P, et al. (2019) The amino acid sensor general control nonderepressible 2 (GCN2) controls TH9 cells and allergic airway inflammation. J Allergy Clin Immunol 144(4):1091-1105 |
| abstractText | BACKGROUND: 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: We sought to clarify the regulatory roles of GCN2 in CD4(+) T-cell subset differentiation and its significance in patients with allergic airway inflammation. METHODS: The effects of GCN2 in differentiation of TH cell subsets were detected by using the in vitro induction system. GCN2 knockout mice, ovalbumin-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 sequencing, real-time PCR, Western blotting, and other molecular approaches were used to identify the molecular mechanisms relevant to regulation of GCN2 in TH9 cell differentiation. RESULTS: GCN2 deficiency significantly inhibited differentiation of TH9 cells but not TH1, TH2, and regulatory T cells. GCN2 knockout mice and recombination-activating 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 on adoptive transfer. Mechanistically, GCN2 deficiency inhibits TH9 cell differentiation through a hypoxia-inducible factor 1alpha-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 might provide novel approaches to attenuate allergic airway inflammation. |
