Early-life undernutrition reprograms CD4⁺ T-cell glycolysis and epigenetics to facilitate asthma - 06/06/19

Doi : 10.1016/j.jaci.2018.12.999

Xi Chen, PhD ^a,^b,^h,^{∗
These authors contributed equally to this work.}, Hui Lin, MD ^a,^b,^{∗
These authors contributed equally to this work.}, Daping Yang, PhD ^c, Wei Xu, PhD ^d, Guangwei Liu, MD ^e, Xinmei Liu, PhD ^a,^b,^h,^⁎,^{‡
These authors contributed equally to this work.} , Jianzhong Sheng, PhD ^f,^⁎,^{‡
These authors contributed equally to this work.} , Hefeng Huang, MD ^a,^b,^g,^h,^⁎,^{‡
These authors contributed equally to this work.}
^a International Peace Maternity & Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
^b Institute of Embryo-Fetal Original Adult Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
^c Key Laboratory of Stem Cell Biology, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
^d Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
^e 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
^f Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Zhejiang, China
^g Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, Zhejiang, China
^h Shanghai Key Laboratory of Embryo Original Disease, Shanghai, China

^∗Corresponding authors: Hefeng Huang, MD, International Peace Maternity & Child Health Hospital, School of Medicine, Shanghai Jiaotong University, No. 1961 Huashan Road, Shanghai 200030, China.International Peace Maternity & Child Health HospitalSchool of MedicineShanghai Jiaotong UniversityNo. 1961 Huashan RoadShanghai200030China^∗Jianzhong Sheng, PhD, School of Medicine, Zhejiang University, No. 866 Yuhangtang Road, Hangzhou, Zhejiang, 310058, China.School of MedicineZhejiang UniversityNo. 866 Yuhangtang RoadHangzhouZhejiang310058China^∗Xinmei Liu, PhD, Institute of Embryo-Fetal Original Adult Disease, School of Medicine, Shanghai Jiaotong University, No. 1961 Huashan Road, Shanghai, 200030, China.Institute of Embryo-Fetal Original Adult DiseaseSchool of MedicineShanghai Jiaotong UniversityNo. 1961 Huashan RoadShanghai200030China

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.

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Graphical abstract

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Key words : Early-life undernutrition, asthma, CD4⁺ T cells, glycolysis, DNA methylation

Abbreviations used : 7-AAD, Arg1, BALF, CNS1, 2-DG, ECAR, FCCP, Fizz1, Hk2, IUGR, Ldha, mTORC, NCD, OCR, OVA, Pkm, PRD, Tpi, Treg, Ym1

Plan

Methods

Mice and diets

T-cell isolation and culture

Flow cytometry

Real-time PCR

Seahorse cellular metabolic profiling

Western blotting

OVA-induced experimental asthma

Lung airway hyperreactivity measurement

Tissue histologic sections

Bisulfite sequencing

Statistical analysis

Results

Early-life undernutrition promotes T-cell activation, proliferation, and glycolysis

mTORC1-dependent glycolysis is responsible for upregulated PRD CD4⁺ T-cell activation and proliferation

PRD naive CD4⁺ T cells are prone to differentiate toward T_H2 in vitro

The CNS1 region of the T_H2 cytokine locus is hypomethylated in naive CD4⁺ T cells under early-life protein restriction

Early-life undernutrition facilitates experimental asthma by promoting T_H2 cell differentiation

Effects of maternal undernutrition on experimental asthma in offspring are mainly mediated in utero

Glycolysis inhibition alleviates early-life undernutrition-induced T_H2 skewing and susceptibility to experimental asthma

Discussion

This study was supported by the National Key Research and Development Program of China (2017YFC1001303 to H.H.), the National Natural Science Foundation of China (31471405 to H.H. and 81671456 to X.L.), the major program of the National Natural Science Foundation of China (81490742 to H.H.), the Shanghai Sailing Program (17YF1420700 to X.C.), the China Postdoctoral Science Foundation (2016M601616 to X.C.), the International Cooperation Project of China and Canada NSFC (81661128010 to H.H.), the Interdisciplinary Key Program of Shanghai Jiao Tong University (YG2014ZD08 to H.H.), and the Shen Kang Three Year Action plan (16CR3003A to H.H.).

Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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Vol 143 - N° 6

P. 2038 - juin 2019 Retour au numéro

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Early-life undernutrition reprograms CD4⁺ T-cell glycolysis and epigenetics to facilitate asthma - 06/06/19

Abstract

Background

Objective

Methods

Results

Conclusion

Graphical abstract

Plan

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