Although inflammatory complications are common in preterm infants, their effects on neonatal immune development remain poorly defined. We therefore investigated whether severe bronchopulmonary dysplasia (BPD) and systemic infection, two major complications of prematurity, produce distinct immune signatures and change immune composition over time. We performed longitudinal high-dimensional immune profiling of residual whole blood from 38 preterm infants sampled every two weeks, along with 10 term infants at birth. Preterm infants with severe BPD showed a progressive increase in Th17-polarized CD4+ T cells, neutrophils, and Th17-related cytokines compared to age-matched infants with moderate BPD. In contrast, some preterm infants with systemic bacterial or viral infections mounted robust CD8+, CD4+, and γδ T cell responses, with oligoclonal expansion, terminal differentiation, and coordinated plasma cytokine shifts that persisted well beyond resolution of infection. These findings demonstrate that different preterm comorbidities imprint the neonatal immune system in divergent ways. Longitudinal immune profiling offers a powerful tool to uncover these trajectories and identify potential targets for intervention.

E.J.W. is a member of the Parker Institute for Cancer Immunotherapy. E.J.W. is an advisor for Arpelos Bio, Arsenal Biosciences, Coherus, Danger Bio, IpiNovyx, New Limit, Marengo, Pluto Immunotherapeutics, Related Sciences, Santa Ana Bio, and Synthekine. E.J.W. is a founder of Arpelos Bio, Arsenal Biosciences, Danger Bio, and holds stock in Coherus. A.R.G. is a consultant for Arsenal Biosciences, Cellanome, GVM1, and Seismic Therapeutics. The remaining authors declare no competing interests.

This study was funded by the Thrasher Early Career Research Award (to B.A.F.), the American Association of Pediatrics (AAP) Marshall Klaus Award (to B.A.F.) and the Division of Neonatology and Childrens Hospital of Philadelphia. This work was also supported by NIH grants AI155577, AI115712, AI117950, AI108545, AI082630, AI149680, HL145754 (to E.J.W.), Parker Institute for Cancer Immunotherapy (to E.J.W.), and The Mark Foundation (to E.J.W.), the Arguild Foundation and philanthropic support to the UPenn Immune Health Innovation fund.

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