T-bet inhibits innate lymphoid cell–mediated eosinophilic airway inflammation by suppressing IL-9 production

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Abstract

Background:

Innate lymphoid cells (ILCs) are emerging subsets of immune cells that produce large amounts of cytokines upon cytokine and/or alarmin stimulation. Recent studies have shown that T-bet plays pivotal roles in the development of ILC3s and type 1 ILCs; however, the roles of T-bet in lung type 2 innate lymphoid cells (ILC2s) remain unknown.

Objective:

We sought to determine the role of T-bet in ILC2-mediated airway inflammation.

Methods:

The expression of T-bet in lung ILCs (defined as Thy1.2+ Lin− cells) was examined. The roles of T-bet in the development of lung ILC2s and airway inflammation induced by IL-33 administration were examined by using T-bet–deficient (T-bet−/−) mice. Gene expression profiles of T-bet−/− lung ILCs were analyzed by RNA sequencing.

Results:

T-bet was expressed in lung ILC2s (defined as Thy1.2+ Lin− cells expressing ST2 or CD25) and IFN-γ enhanced its expression. Although the development of lung ILC2s at steady-state conditions was normal in T-bet−/− mice, IL-33–induced accumulation of lung ILC2s and eosinophilic airway inflammation were exacerbated in T-bet−/− mice. The exacerbated accumulation of ILC2s and eosinophilic airway inflammation by the absence of T-bet were evident even in a RAG2−/− background, suggesting that T-bet expressed in non–T/non–B population is involved in the suppression of IL-33–induced eosinophilic airway inflammation. Transcriptome analysis revealed that IL-9 expression in IL-33–stimulated lung ILCs was upregulated in T-bet−/− mice compared with that in wild-type mice. Importantly, neutralization of IL-9 markedly attenuated IL-33–induced accumulation of lung ILC2s and eosinophilic inflammation in T-bet−/− mice.

Conclusions:

T-bet suppresses IL-9 production from lung ILC2s and thereby inhibits IL-33–induced eosinophilic airway inflammation.

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