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

Abstract

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. 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. 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. 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. 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.