Abstract
Regulatory T cells (Tregs) are important for the ontogenetic control of immune activation and tissue damage in preterm infants. However, the role of Tregs for the development of bronchopulmonary dysplasia (BPD) is yet unclear. The aim of our study was to characterize CD4+ CD25+ forkhead box protein 3 (FoxP3)+ Tregs in peripheral blood of well-phenotyped preterm infants (n = 382; 23 + 0 – 36 + 6 weeks of gestational age) with a focus on the first 28 days of life and the clinical endpoint BPD (supplemental oxygen for longer than 28 days of age). In a subgroup of preterm infants, we characterized the immunological phenotype of Tregs (n = 23). The suppressive function of Tregs on CD4+CD25- T cells was compared in preterm, term and adult blood. We observed that extreme prematurity was associated with increased Treg frequencies which peaked in the second week of life. Independent of gestational age, increased Treg frequencies were noted to precede the development of BPD. The phenotype of preterm infant Tregs largely differed from adult Tregs and displayed an overall naïve Treg population (CD45RA+/HLA-DR-/Helios+), especially in the first days of life. On day 7 of life, a more activated Treg phenotype pattern (CCR6+, HLA-DR+, and Ki-67+) was observed. Tregs of preterm neonates had a higher immunosuppressive capacity against CD4+CD25- T cells compared to the Treg compartment of term neonates and adults. In conclusion, our data suggest increased frequencies and functions of Tregs in preterm neonates which display a distinct phenotype with dynamic changes in the first weeks of life. Hence, the continued abundance of Tregs may contribute to sustained inflammation preceding the development of BPD. Functional analyses are needed in order to elucidate whether Tregs have potential as future target for diagnostics and therapeutics.
Highlights
Bronchopulmonary dysplasia (BPD) is a major complication of premature birth and has been linked to chronic pulmonary inflammation leading to a high risk of mortality and long-term morbidities [1,2,3,4,5]
The suppressive capacity was shown to be dependent on the number of Tregs in the co-culture, since a 2:1 ratio of CD4+CD25– T cells to Tregs led to higher proliferation rates compared to a 1:1 cell ratio within the different groups of preterm, term and adult derived Tregs (Figure 4). In this single-center prospective longitudinal study we demonstrated that increased Treg frequencies in the first 2 weeks of life precede the development of bronchopulmonary dysplasia (BPD) in preterm infants
After birth a naïve Treg population (CD45RA+/Helios+) is dominating while a more activated Treg phenotype pattern (CCR6+, HLA-DR+, Ki-67+) develops in the second week of life accompanied by a peak in the Treg frequencies
Summary
Bronchopulmonary dysplasia (BPD) is a major complication of premature birth and has been linked to chronic pulmonary inflammation leading to a high risk of mortality and long-term morbidities [1,2,3,4,5]. We hypothesize that regulatory T cells (Treg) including their immunological phenotype and immunosuppressive capacities play a pivotal role for pathways of BPD development. This hypothesis is supported by several aspects. The immune functions of the semi-allogeneic fetus are adapted to prevent potentially damaging inflammation, which leads to temporary immunosuppression in the neonatal period. This ontogenetic specificity may enable colonization of the commensal microbiota to be tolerated after birth and avoids inflammatory tissue damage [11], it might predispose the neonate to infection. We tested the suppressive Treg capacity from preterm infants in comparison with term neonates and adults
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