The amino acid sensor general control nonderepressible 2 (GCN2) controls T9 cells and allergic airway inflammation.

BACKGROUND

T9 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 T 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 T9 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 T9 cell differentiation.

RESULTS

GCN2 deficiency significantly inhibited differentiation of T9 cells but not T1, T2, 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 T9 differentiation and less severe allergic airway inflammation. Furthermore, the isolated GCN2-deficient T9 cells also mediated less severe allergic airway inflammation on adoptive transfer. Mechanistically, GCN2 deficiency inhibits T9 cell differentiation through a hypoxia-inducible factor 1α-dependent glycolytic pathway.

CONCLUSION

Our results reveal a novel role of GCN2 in T9 cell differentiation. Our findings indicate that new strategies to inhibit GCN2 activity might provide novel approaches to attenuate allergic airway inflammation.