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J Allergy Clin Immunol. 2019 Aug;144(2):549-560.e10. doi: 10.1016/j.jaci.2019.02.024. Epub 2019 Mar 7.

Ezh2 controls development of natural killer T cells, which cause spontaneous asthma-like pathology.

Author information

1
Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan; Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia. Electronic address: damon.tumes@unisa.edu.au.
2
Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.
3
Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, Australia.
4
Deutsches Rheuma-Forschungszentrum Berlin, Leibniz Institute, Berlin, Germany.

Abstract

BACKGROUND:

Natural killer T (NKT) cells express a T-cell receptor that recognizes endogenous and environmental glycolipid antigens. Several subsets of NKT cells have been identified, including IFN-γ-producing NKT1 cells, IL-4-producing NKT2 cells, and IL-17-producing NKT17 cells. However, little is known about the factors that regulate their differentiation and respective functions within the immune system.

OBJECTIVE:

We sought to determine whether the polycomb repressive complex 2 protein enhancer of zeste homolog 2 (Ezh2) restrains pathogenicity of NKT cells in the context of asthma-like lung disease.

METHODS:

Numbers of invariant natural killer T (iNKT) 1, iNKT2, and iNKT17 cells and tissue distribution, cytokine production, lymphoid tissue localization, and transcriptional profiles of iNKT cells from wild-type and Ezh2 knockout (KO) iNKT mice were determined. The contribution of NKT cells to development of spontaneous and house dust mite-induced airways pathology, including airways hyperreactivity (AHR) to methacholine, was also assessed in wild-type, Ezh2 KO, and Ezh2 KO mice lacking NKT cells.

RESULTS:

Ezh2 restrains development of pathogenic NKT cells, which induce spontaneous asthma-like disease in mice. Deletion of Ezh2 increased production of IL-4 and IL-13 and induced spontaneous AHR, lung inflammation, mucus production, and IgE. Increased IL-4 and IL-13 levels, AHR, lung inflammation, and IgE levels were all dependent on iNKT cells. In house dust mite-exposed animals Ezh2 KO resulted in enhanced AHR that was also dependent on iNKT cells.

CONCLUSION:

Ezh2 is a central regulator of iNKT pathogenicity and suppresses the ability of iNKT cells to induce asthma-like pathology.

KEYWORDS:

Asthma; allergy; epigenetics; inflammation; natural killer T cells

PMID:
30851295
DOI:
10.1016/j.jaci.2019.02.024

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