Histone demethylases UTX and JMJD3 are required for NKT cell development in mice

Daniel Northrup,Chaochen Wang,Kai Ge,Lance R Pohl,Keji Zhao,Rongfu Wang,William R Proctor,Ryoji Yagi,Jinfang Zhu,Kairong Cui,Katarzyna Placek

doi:10.1186/s13578-017-0152-8

Abstract

BackgroundNatural killer (NK)T cells and conventional T cells share phenotypic characteristic however they differ in transcription factor requirements and functional properties. The role of histone modifying enzymes in conventional T cell development has been extensively studied, little is known about the function of enzymes regulating histone methylation in NKT cells.ResultsWe show that conditional deletion of histone demethylases UTX and JMJD3 by CD4-Cre leads to near complete loss of liver NKT cells, while conventional T cells are less affected. Loss of NKT cells is cell intrinsic and not due to an insufficient selection environment. The absence of NKT cells in UTX/JMJD3-deficient mice protects mice from concanavalin A‐induced liver injury, a model of NKT‐mediated hepatitis. GO‐analysis of RNA-seq data indicates that cell cycle genes are downregulated in UTX/JMJD3-deleted NKT progenitors, and suggest that failed expansion may account for some of the cellular deficiency. The phenotype appears to be demethylase‐dependent, because UTY, a homolog of UTX that lacks catalytic function, is not sufficient to restore their development and removal of H3K27me3 by deletion of EZH2 partially rescues the defect.ConclusionsNKT cell development and gene expression is sensitive to proper regulation of H3K27 methylation. The H3K27me3 demethylase enzymes, in particular UTX, promote NKT cell development, and are required for effective NKT function.

Highlights

Natural killer (NK)T cells and conventional T cells share phenotypic characteristic they differ in transcription factor requirements and functional properties
T cell development is slightly altered after the loss of UTX, JMJD3 or both To examine whether UTX and JMJD3 contribute to T cell development, we analyzed the CD4 and CD8 T cell populations from the spleens of the three knockout mouse strains by flow cytometry (Fig. 1a, left panels)
We found that UTX and JMJD3 are required for the development of natural killer T (NKT) cells, while conventional T cell development is less affected

Summary

Introduction

Natural killer (NK)T cells and conventional T cells share phenotypic characteristic they differ in transcription factor requirements and functional properties. Many NKT cells utilize a characteristic Vα‐Jα rearrangement with limited TCRβ repertoire. This TCR can be stimulated by a lipid molecule, α‐Galactosyl ceramide (αGalCer), presented by CD1d, and is selected on self‐lipid‐CD1d determinants [3]. They are capable of rapid secretion of a wide variety of cytokines [4]. Because of their fast action and access to the blood stream they are important cellular components of pathogenic inflammation in the liver and lung, and fight cancer and infection during innate immune responses [3, 5]

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