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

Publication date: Available online 15 January 2019

Source: Journal of Allergy and Clinical Immunology

Author(s): Xi Chen, Hui Lin, Daping Yang, Wei Xu, Guangwei Liu, Xinmei Liu, Jianzhong Sheng, Hefeng Huang

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 impacts 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. Naïve CD4⁺ T cells (CD4⁺CD62L^hiCD44^-) from offspring were used throughout the study. Type 2 T helper (Th2) differentiation was examined by FACS and ELISA under Th2-polarized conditions in vitro and by ovalbumin (OVA)-induced experimental asthma in vivo. T-cell metabolism was measured with a Seahorse XF96 Analyzer. DNA methylation levels were measured by bisulfite sequencing.

Results

PRD CD4⁺ T cells displayed increased activation and proliferation and were prone to differentiate into Th2 cells both in vitro and in vivo, leading to susceptibility to experimental asthma. Mechanistically, early life undernutrition upregulated mTORC1- dependent glycolysis and induced conserved noncoding DNA sequence 1 (CNS1) DNA hypomethylation in Th2 cytokine locus of CD4⁺ T cells. Glycolysis blockades undermined increased Th2 skewing and alleviated experimental asthma in PRD mice.

Conclusion

Early life undernutrition induced mTORC1-dependent glycolysis upregulation and Th2 cytokine locus hypomethylation in CD4⁺ T cells, resulting in increased T-cell activation, proliferation and Th2 skewing and further susceptibility to experimental asthma.

Graphical abstract

http://bit.ly/2CixoLq