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

• Published in: Journal of allergy and clinical immunology 2019-08, Vol.144 (2), p.549-560.e10
• Main Authors: Tumes, Damon, Hirahara, Kiyoshi, Papadopoulos, Magdalene, Shinoda, Kenta, Onodera, Atsushi, Kumagai, Jin, Yip, Kwok Ho, Pant, Harshita, Kokubo, Kota, Kiuchi, Masahiro, Aoki, Ami, Obata-Ninomiya, Kazushige, Tokoyoda, Koji, Endo, Yusuke, Kimura, Motoko Y., Nakayama, Toshinori
• Format: Article
• Language: English
• Subjects: Allergies; allergy; Animals; Antigens; Asthma; Asthma - genetics; Asthma - immunology; Asthma - pathology; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - immunology; Clonal deletion; Cloning; Cytokines; Dust; Enhancer of Zeste Homolog 2 Protein - genetics; Enhancer of Zeste Homolog 2 Protein - immunology; Epigenetics; Homology; House dust; Human subjects; Hyperreactivity; Hypersensitivity; Immune system; Immunoglobulin E; Immunoglobulin E - genetics; Immunoglobulin E - immunology; Inflammation; Inflammation - genetics; Inflammation - immunology; Inflammation - pathology; Interleukin 13; Interleukin 17; Interleukin 4; Interleukin-13 - genetics; Interleukin-13 - immunology; Interleukin-4 - genetics; Interleukin-4 - immunology; Laboratories; Localization; Lung - immunology; Lung - pathology; Lung diseases; Lymphocytes; Lymphocytes T; Lymphoid tissue; Methacholine; Mice; Mice, Knockout; Mites; Mucus; Natural killer cells; natural killer T cells; Natural Killer T-Cells - immunology; Natural Killer T-Cells - pathology; Pathogenicity; Pathogens; Pathology; Polycomb group proteins; Proteins; Receptors, Aryl Hydrocarbon - genetics; Receptors, Aryl Hydrocarbon - immunology; T cell receptors; Transcription; Transcription factors; γ-Interferon
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2019.02.024

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