T-bet inhibits innate lymphoid cell-mediated eosinophilic airway inflammation by suppressing IL-9 production.
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.
Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Ayako
A
Matsuki
Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan. Electronic address: takatorih@faculty.chiba-u.jp.
Hiroaki
H
Takatori
Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Sohei
S
Makita
Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Masaya
M
Yokota
Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Tomohiro
T
Tamachi
Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Akira
A
Suto
Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Kotaro
K
Suzuki
Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Koichi
K
Hirose
Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan. Electronic address: nakajimh@faculty.chiba-u.jp.
Hiroshi
H
Nakajima
D000818:Animals; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000276:immunology*; D000067596:Interleukin-33 / Q000096:biosynthesis / Q000276:immunology; D016906:Interleukin-9 / Q000096:biosynthesis* / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011657:Pulmonary Eosinophilia / Q000276:immunology / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000276:immunology* / Q000378:metabolism; D018800:Thy-1 Antigens; D000098815:T-bet Transcription Factor
D000067596:Interleukin-33; D016906:Interleukin-9; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018800:Thy-1 Antigens
IL-9; T-bet; eosinophils; innate lymphoid cells