Perturbation of the preterm human immune system in early life
Benjamin A. Fensterheim, Michelle L. McKeague, Divij Mathew, Shwetank, Ajinkya Pattekar, Matthew Lee, Zahabia Rangwala, Sean Nasta, Macy C. Kee, Cynthia Clendenin, Zachary Martinez, Caroline Diorio, Allison R. Greenplate, Krithika Lingappan, E. John Wherry
Benjamin A. Fensterheim, Michelle L. McKeague, Divij Mathew, Shwetank, Ajinkya Pattekar, Matthew Lee, Zahabia Rangwala, Sean Nasta, Macy C. Kee, Cynthia Clendenin, Zachary Martinez, Caroline Diorio, Allison R. Greenplate, Krithika Lingappan, E. John Wherry
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Research Article Development Immunology Inflammation

Perturbation of the preterm human immune system in early life

Abstract

Although inflammatory complications are common in preterm infants, the effects of these conditions on neonatal immune development remain poorly defined. We therefore investigated whether severe bronchopulmonary dysplasia (BPD) and systemic infection, 2 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 2 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 with age-matched infants with moderate BPD. In contrast, some preterm infants with systemic bacterial or viral infections mounted exceptionally 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. Thus, comprehensive and longitudinal immune profiling may not only identify connections between clinical inflammatory complications and underlying immune pathways but also reveal potential targets for intervention.

Authors

Benjamin A. Fensterheim, Michelle L. McKeague, Divij Mathew, Shwetank, Ajinkya Pattekar, Matthew Lee, Zahabia Rangwala, Sean Nasta, Macy C. Kee, Cynthia Clendenin, Zachary Martinez, Caroline Diorio, Allison R. Greenplate, Krithika Lingappan, E. John Wherry

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Figure 2

Postnatal life alters the gestational immune trajectory in preterm infants.

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Postnatal life alters the gestational immune trajectory in preterm infan...
Linear mixed models were generated for each cell and cytokine. (A and B) The difference of the scaled slopes from the regression generated from all preterm samples and the regression generated from only at-birth samples, for each cell and for each cytokine. Cell types above the center dashed line represent populations whose slope increases compared with the expected gestational age progression for that cell type at birth, and cell types below the center dotted line represent populations whose slope decreases. Color intensity of the dots (red increased in postnatal life, blue decreased) represents the strength of the slope deviation. Significance set at P < 0.01 of BH-adjusted P values as determined by the difference in slopes of the 2 linear models. (C) Models of specific cell populations neutrophils, CD161+CD8+ T cells, naive CD8+ T cells, naive γδ T cells, and naive CD4+ T cells, as well as cytokines FGF-21, RANKL, and VEGF-A, across cGA time. For each plot, the solid black line represents the regression derived from all collected preterm samples. The red dashed line represents the regression derived from the at-birth term and preterm samples only, as calculated in Figure 1. Each dot color corresponds to a single preterm infant, and the small, dashed lines connect serial samples collected from the same infant over time.