Early-life undernutrition reprograms CD4+ T-cell glycolysis and epigenetics to facilitate asthma

Xi Chen; Hui Lin; Daping Yang; Wei Xu; Guangwei Liu; Xinmei Liu; Jianzhong Sheng; Hefeng Huang

doi:10.1016/j.jaci.2018.12.999

Early-life undernutrition reprograms CD4⁺ T-cell glycolysis and epigenetics to facilitate asthma

J Allergy Clin Immunol. 2019 Jun;143(6):2038-2051.e12. doi: 10.1016/j.jaci.2018.12.999. Epub 2019 Jan 15.

Authors

Xi Chen¹, Hui Lin², Daping Yang³, Wei Xu⁴, Guangwei Liu⁵, Xinmei Liu⁶, Jianzhong Sheng⁷, Hefeng Huang⁸

Affiliations

¹ International Peace Maternity & Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Embryo-Fetal Original Adult Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Embryo Original Disease, Shanghai, China.
² International Peace Maternity & Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Embryo-Fetal Original Adult Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
³ Key Laboratory of Stem Cell Biology, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
⁴ Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
⁵ Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China.
⁶ International Peace Maternity & Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Embryo-Fetal Original Adult Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Embryo Original Disease, Shanghai, China. Electronic address: nanlilac@hotmail.com.
⁷ Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Zhejiang, China. Electronic address: shengjz@zju.edu.cn.
⁸ International Peace Maternity & Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Embryo-Fetal Original Adult Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, Zhejiang, China; Shanghai Key Laboratory of Embryo Original Disease, Shanghai, China. Electronic address: huanghefg@sjtu.edu.cn.

PMID: 30654047
DOI: 10.1016/j.jaci.2018.12.999

Abstract

Background: Exposure to early-life undernutrition is closely related to higher risks of adverse immunologic outcomes in adulthood. Although it has been suggested that asthma has its origins in early life, its underlying mechanisms remain largely unknown.

Objective: We characterized the effects of early-life undernutrition on T lymphocytes, which play a pivotal role in immune diseases, and we investigated whether this contributes to susceptibility to asthma in adulthood.

Methods: Pregnant mice were fed a protein restriction diet (PRD) to establish an early-life undernutrition model. Naive CD4⁺ T cells (CD4⁺CD62L^hiCD44^-) from offspring were used throughout the study. T_H2 differentiation was examined by using fluorescence-activated cell sorting and ELISA under T_H2-polarized conditions in vitro and through ovalbumin-induced experimental asthma in vivo. T-cell metabolism was measured with a Seahorse XF96 Analyzer. DNA methylation levels were measured by using bisulfite sequencing.

Results: PRD CD4⁺ T cells displayed increased activation and proliferation and were prone to differentiate into T_H2 cells both in vitro and in vivo, leading to susceptibility to experimental asthma. Mechanistically, early-life undernutrition upregulated mechanistic target of rapamycin 1-dependent glycolysis and induced conserved noncoding DNA sequence 1 DNA hypomethylation in the T_H2 cytokine locus of CD4⁺ T cells. Glycolysis blockades undermined increased T_H2 skewing and alleviated experimental asthma in PRD mice.

Conclusion: Early-life undernutrition induced mechanistic target of rapamycin 1-dependent glycolysis upregulation and T_H2 cytokine locus hypomethylation in CD4⁺ T cells, resulting in increased T-cell activation, proliferation, and T_H2 skewing and further susceptibility to experimental asthma.

Keywords: CD4(+) T cells; DNA methylation; Early-life undernutrition; asthma; glycolysis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allergens / immunology
Animals
Asthma / genetics*
Asthma / immunology*
CD4-Positive T-Lymphocytes / immunology*
Cytokines / genetics
Cytokines / immunology
Epigenesis, Genetic
Female
Glycolysis
Lung / immunology
Lung / physiopathology
Male
Malnutrition / genetics*
Malnutrition / immunology*
Mechanistic Target of Rapamycin Complex 1 / immunology
Mechanistic Target of Rapamycin Complex 2 / immunology
Mice, Inbred C57BL
Ovalbumin / immunology
Pregnancy

Substances

Allergens
Cytokines
Ovalbumin
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2