The amino acid sensor general control nonderepressible 2 (GCN2) controls T_H9 cells and allergic airway inflammation.

Abstract

T_H9 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. We sought to clarify the regulatory roles of GCN2 in CD4⁺ T-cell subset differentiation and its significance in patients with allergic airway inflammation. The effects of GCN2 in differentiation of T_H 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 T_H9 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 T_H9 cell differentiation. GCN2 deficiency significantly inhibited differentiation of T_H9 cells but not T_H1, T_H2, 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 T_H9 differentiation and less severe allergic airway inflammation. Furthermore, the isolated GCN2-deficient T_H9 cells also mediated less severe allergic airway inflammation on adoptive transfer. Mechanistically, GCN2 deficiency inhibits T_H9 cell differentiation through a hypoxia-inducible factor 1α-dependent glycolytic pathway. Our results reveal a novel role of GCN2 in T_H9 cell differentiation. Our findings indicate that new strategies to inhibit GCN2 activity might provide novel approaches to attenuate allergic airway inflammation.