Premature birth and Cesarean section are associated with significant differences in neonatal CD4+ T cell gene expression and function

Abstract Premature birth and cesarean section are associated with increased morbidity and inflammatory diseases. However, their impact on neonatal immunity remains incompletely defined. To explore how gestational age and mode of delivery contribute to early immune programming, we analyzed CD4+ T cells, central regulators of adaptive responses, from preterm neonates and full-term neonates born by cesarean section or vaginal delivery. We performed transcriptomic profiling (mRNA-seq) and functional assessment of T cell activation, proliferation, and cytokine production following stimulation. The mode of delivery emerged as a key factor for CD4+ T cell transcriptome and function. CD4+ T cells from full-term neonates born by vaginal delivery exhibited an immune activation signature, produced higher levels of multiple cytokines, and showed reduced proliferative capacity. In contrast, prematurity was associated with modest changes in basal gene expression relative to full-term cesarean section neonates. CD4+ T cells from preterm neonates displayed enhanced proliferation and increased secretion of inflammatory cytokines (IL-13, TNFα, IL-6, and IL-17F) upon stimulation, consistent with heightened responsiveness. Collectively, our findings show that CD4+ T cells from preterm neonates exhibit augmented inflammatory potential, which becomes more regulated at term. Mode of delivery further contributes to this developmental trajectory: cesarean section is associated with a restrained functional profile, whereas vaginal delivery is associated with a mild immune activation signature and increased responsiveness. These results support a model in which neonatal CD4+ T cell trajectories are established during fetal life and further modulated at birth, highlighting the layered influence of perinatal factors on immune development.