Ezh2 Controls Development of Natural Killer T Cells, Which Cause Spontaneous Asthma-Like Pathology

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma / genetics
  • Asthma / immunology*
  • Asthma / pathology
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / immunology
  • Enhancer of Zeste Homolog 2 Protein / genetics
  • Enhancer of Zeste Homolog 2 Protein / immunology*
  • Immunoglobulin E / genetics
  • Immunoglobulin E / immunology
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / pathology
  • Interleukin-13 / genetics
  • Interleukin-13 / immunology
  • Interleukin-4 / genetics
  • Interleukin-4 / immunology
  • Lung / immunology*
  • Lung / pathology
  • Mice
  • Mice, Knockout
  • Natural Killer T-Cells / immunology*
  • Natural Killer T-Cells / pathology
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / immunology

Substances

  • Ahr protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Il4 protein, mouse
  • Interleukin-13
  • Receptors, Aryl Hydrocarbon
  • Interleukin-4
  • Immunoglobulin E
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse