Maturation-Dependent Constraints in the Ability of Human Monocytes to Initiate Trained Immunity

The survival of nonvertebrate species that lack adaptive immunity has prompted the discovery of memory mechanisms in innate immune cells, termed trained immunity. Because infants depend on innate immunity to fight off pathogens, leveraging these mechanisms in neonatal care may hold clinical significance. Yet, this is constrained by limited understanding of innate immune memory development during early-life. By performing systems-level characterization of β-glucan-trained monocytes from adults, term infants, and preterm infants, we report maturation-dependent constraints in trained immunity. We corroborate these findings in a small cohort of premature infants with in utero pathogen exposure. Alongside limited stimulus-induced reprogramming of innate immune responses in the clinical cohort, monocytes from premature infants exhibited metabolic alterations in glutaminolysis and tricarboxylic acid cycle metabolism, pathways central to trained immunity. They also displayed a treatment-robust long noncoding RNA landscape and transcriptional alterations in enzymes relevant to epigenetic induction of innate immune memory. Finally, network-based analyses implicated SMAD5 and ARNT as potential drivers of differences and provided evidence for altered transcriptional regulation of chromatin organization across early-life development. Our results suggest that metabolic and transcriptomic immaturity constrains trained immunity in premature infants, highlighting a developmental mechanism that may affect host defense and guide future immunomodulatory strategies.