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Premature birth and cesarean section affect neonatal CD4+ T cell gene expression and cellular function

ABSTRACT: Premature birth and cesarean section are major perinatal factors influencing immune development and are associated with increased morbidity and inflammatory diseases. However, their impact on neonatal adaptive immunity remains incompletely understood. To determine how gestational age and mode of delivery shape early immune programming, we analyzed CD4⁺ T cells, central regulators of adaptive responses, from preterm neonates (28–36 wga) and full-term neonates delivered by cesarean section or natural birth. We performed transcriptomic profiling by mRNA sequencing, complemented by functional assessment of T cell activation, proliferation, and cytokine production following stimulation. The mode of delivery exerted a dominant effect on the CD4⁺ T cell transcriptome and function. CD4⁺ T cells from full-term neonates delivered by natural birth exhibited an immune activation signature compared with those from cesarean section and produced higher levels of multiple cytokines, but showed reduced proliferative capacity. In contrast, prematurity induced modest changes in basal gene expression relative to full-term cesarean section neonates. Despite these limited transcriptional differences, CD4⁺ Tcells from preterm neonates displayed enhanced proliferation and increased secretion of inflammatory cytokines IL-13, TNFα, IL-6, and IL-17F, indicating heightened responsiveness. Collectively, our findings suggest that CD4⁺ T cell immune programming begins in utero, as preterm neonates exhibit heightened inflammatory responsiveness. At term, the mode of delivery further refines this developmental trajectory. Cesarean section is associated with a restrained functional profile, whereas natural birth induces an immune activation signature and enhanced cytokine production. These results provide functional evidence that neonatal CD4⁺ T cell trajectories are established during fetal life and subsequently modulated at birth, underscoring the layered influence of perinatal factors on immune development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE322854 | GEO | 2026/07/30

REPOSITORIES: GEO

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Project description:Chorioamnionitis (CA), resulting from intra-amniotic inflammation, is a frequent cause of preterm birth and exposes the immature intestine to bacterial toxins and/or inflammatory mediators before birth via fetal swallowing. This may affect intestinal immune development, interacting with the effects of enteral feeding and gut microbiota colonization just after birth. Using preterm pigs as model for preterm infants, we hypothesized that prenatal exposure to gram-negative endotoxin influences postnatal bacterial colonization and gut immune development. Pig fetuses were given intra-amniotic lipopolysaccharide (LPS) 3 d before preterm delivery by cesarean section, and were compared with litter-mate controls (CON) at birth and after 5 d of formula feeding and spontaneous bacterial colonization. Amniotic fluid was collected for analysis of leukocyte counts and cytokines, and the distal small intestine was analyzed for endotoxin level, morphology and immune cell counts. Intestinal gene expression and microbiota were analyzed by transcriptomics and metagenomics, respectively. At birth, LPS-exposed pigs showed higher intestinal endotoxin, neutrophil/macrophage density and shorter villi. About 1.0% of intestinal genes were affected at birth and DMBT1, a regulator of mucosal immune defense, was identified as the hub gene in the co-expression network. Genes related to innate immune response (TLR2, LBP, CD14, C3, SFTPD), neutrophil chemotaxis (C5AR1, CSF3R, CCL5) and antigen processing (MHC II, CD4) were also affected and expression levels correlated with intestinal neutrophil/macrophage density and amniotic fluid cytokine levels. On day 5, LPS and CON pigs showed similar necrotizing enterocolitis (NEC) lesions, endotoxin levels, morphology, immune cell counts, gene expressions and microbiota (except for difference in some low-abundant species). Our results show that CA markedly affects intestinal genes at preterm birth, including genes related to immune cell infiltration. However, a few days later, following the physiological adaptations to preterm birth, CA had limited effects on intestinal structure, function, gene expression, bacterial colonization and NEC sensitivity. We conclude that short-term, prenatal intra-amniotic inflammation is unlikely to exert marked effects on intestinal immune development in preterm neonates beyond the immediate neonatal period.

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Premature birth and cesarean section affect neonatal CD4+ T cell gene expression and cellular function

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