Differential Expression of the Transcription Factor GATA3 Specifies Lineage and Functions of Innate Lymphoid Cells

Chao Zhong; Mingzhu Zheng; Kairong Cui; Andrew J Martins; Gangqing Hu; Dan Li; Lino Tessarollo; Serguei Kozlov; Jonathan R Keller; John S Tsang; Keji Zhao; Jinfang Zhu

doi:10.1016/j.immuni.2019.12.001

Differential Expression of the Transcription Factor GATA3 Specifies Lineage and Functions of Innate Lymphoid Cells

Immunity. 2020 Jan 14;52(1):83-95.e4. doi: 10.1016/j.immuni.2019.12.001. Epub 2019 Dec 24.

Authors

Chao Zhong¹, Mingzhu Zheng², Kairong Cui³, Andrew J Martins², Gangqing Hu⁴, Dan Li⁵, Lino Tessarollo⁶, Serguei Kozlov⁷, Jonathan R Keller⁸, John S Tsang², Keji Zhao³, Jinfang Zhu⁹

Affiliations

¹ Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Institute of Systems Biomedicine, Department of Immunology, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100191, PRC. Electronic address: zhongc@hsc.pku.edu.cn.
² Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
³ Laboratory of Epigenome Biology, Systems Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁴ Laboratory of Epigenome Biology, Systems Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; Department of Microbiology, Immunology, and Cell Biology, School of Medicine, West Virginia University, Morgantown, WV 26506, USA.
⁵ Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PRC; Department of Clinical Laboratory, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, PRC.
⁶ Mouse Cancer Genetics Program, Center for Cancer Research, NCI, Frederick, MD 21702, USA.
⁷ Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
⁸ Mouse Cancer Genetics Program, Center for Cancer Research, NCI, Frederick, MD 21702, USA; Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
⁹ Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: jfzhu@niaid.nih.gov.

Abstract

Lymphoid tissue inducer (LTi) cells are regarded as a subset of innate lymphoid cells (ILCs). However, these cells are not derived from the ILC common progenitor, which generates other ILC subsets and is defined by the expression of the transcription factor PLZF. Here, we examined transcription factor(s) determining the fate of LTi progenitors versus non-LTi ILC progenitors. Conditional deletion of Gata3 resulted in the loss of PLZF⁺ non-LTi progenitors but not the LTi progenitors that expressed the transcription factor RORγt. Consistently, PLZF⁺ non-LTi progenitors expressed high amounts of GATA3, whereas GATA3 expression was low in RORγt⁺ LTi progenitors. The generation of both progenitors required the transcriptional regulator Id2, which defines the common helper-like innate lymphoid progenitor (ChILP), but not cytokine signaling. Nevertheless, low GATA3 expression was necessary for the generation of functionally mature LTi cells. Thus, differential expression of GATA3 determines the fates and functions of distinct ILC progenitors.

Keywords: cell fate bifurcation; gene expression; innate lymphoid cell; lineage commitment; lymphocyte development; lymphoid tissue inducer; lymphopoiesis; progenitor heterogeneity; transcription factor; transcriptional regulation.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Lineage / immunology
Cells, Cultured
GATA3 Transcription Factor / biosynthesis*
GATA3 Transcription Factor / genetics
Inhibitor of Differentiation Protein 2 / metabolism
Interleukin Receptor Common gamma Subunit / genetics
Mice
Mice, Inbred C57BL
Mice, Knockout
Nuclear Receptor Subfamily 1, Group F, Member 3 / biosynthesis
Programmed Cell Death 1 Receptor / biosynthesis
Promyelocytic Leukemia Zinc Finger Protein / biosynthesis
Stem Cells / cytology*
Stem Cells / immunology
T-Lymphocyte Subsets / cytology*
T-Lymphocyte Subsets / immunology
T-Lymphocytes, Helper-Inducer / cytology*
T-Lymphocytes, Helper-Inducer / immunology*

Substances

GATA3 Transcription Factor
Gata3 protein, mouse
Idb2 protein, mouse
Il2rg protein, mouse
Inhibitor of Differentiation Protein 2
Interleukin Receptor Common gamma Subunit
Nuclear Receptor Subfamily 1, Group F, Member 3
Pdcd1 protein, mouse
Programmed Cell Death 1 Receptor
Promyelocytic Leukemia Zinc Finger Protein
Rorc protein, mouse
Zbtb16 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding