Phenotypic and Epigenetic Adaptations of Cord Blood CD4+ T Cells to Maternal Obesity

Abstract

Pregravid obesity has been shown to disrupt the development of the offspring’s immune system and increase susceptibility to infection. While the mechanisms underlying the impact of maternal obesity on fetal myeloid cells are emerging, the consequences for T cells remain poorly defined. In this study, we collected umbilical cord blood samples from infants born to lean mothers and mothers with obesity and profiled CD4 T cells using flow cytometry and single cell RNA sequencing at resting and following ex vivo polyclonal stimulation. We report that maternal obesity is associated with higher frequencies of memory CD4 T cells suggestive of in vivo activation. Moreover, single cell RNA sequencing revealed expansion of an activated subset of memory T cells with maternal obesity. However, ex vivo stimulation of purified CD4 T cells resulted in poor cytokine responses, suggesting functional defects. These phenotypic and functional aberrations correlated with methylation and chromatin accessibility changes in loci associated with lymphocyte activation and T cell receptor signaling, suggesting a possible link between maternal obesogenic environment and fetal immune reprogramming. These observations offer a potential explanation for the increased susceptibility to microbial infection in babies born to mothers with obesity.

Impact of pregravid obesity on anti-microbial fetal monocyte response

“…Additionally, within monocytes, pregravid obesity was associated with elevated non-classical monocyte subset (CD16+) ( Supp Figure 1D ). Despite this increase, UCB monocytes from the obese group responded poorly to ex vivo LPS (TLR4 agonist) stimulation ( Supp Figure 1D ), recapitulating the phenotype observed in previously reported studies ( 15, 27, 28, 37 ).…”

“…We began by characterizing immune cell composition and phenotypes in cord blood of subjects stratified by their pre-pregnancy body mass index (BMI) -babies born to lean mothers (BMI <25) and babies born to mothers with obesity (BMI >30). As previously reported, maternal obesity did not alter the frequencies of white blood cells (WBC) or their subsets in the cord blood (15,27,28,37) (Supp Figure 1A). Additionally, no changes were observed in cord blood plasma levels of inflammatory markers (IL-6, CRP) or insulin (Supp Figure 1B-C).…”

“…The transgenerational impact of maternal obesity on the epigenome of the offspring’s immune system has been long appreciated. Several studies have highlighted alterations in methylome and chromatin accessibility landscape of the offspring’s circulating immune cells that are evident as early as at birth ( 15, 27, 38, 48, 56 ). Alterations in promoter regions of DNA methylation in fetal monocytes parallel their dampened expression of anti-inflammatory mediators and attenuated response to M1/M2 polarizing stimuli ( 30 ).…”

“…Moreover, monocytes from offspring of mothers with obesity showed a decrease in transcripts of the pro-inflammatory cytokines IL-1ß and IL-12ß ( 30 ). These dampened CD4 + T cell and monocyte responses are mediated by epigenetic changes at key loci that regulate inflammatory responses and cellular differentiation pathways ( 27, 28 ). Other studies have reported an increased expression of PPAR-γ, which can attenuate macrophage inflammatory responses ( 31 ) in peripheral blood mononuclear cells (PBMCs) obtained from children born to mothers with obesity ( 32 ).…”

“…These observations suggest that pregravid obesity disrupts the development and maturation of the offspring's immune system in utero. Indeed, clinical studies showed that high pregravid BMI is associated with reduced frequency of umbilical cord blood (UCB) CD4 + T cells and dampened CD4 + T cell responses to polyclonal stimulation (15,(27)(28)(29). Additionally, pregravid obesity was associated with a reduced ability of human UCB CD14 + monocytes to respond to ex vivo stimulation with toll-like receptor (TLR) ligands (15,28).…”