Expression of immune checkpoint molecules on adult and neonatal T-cells.

Term and especially preterm neonates are much more susceptible to serious bacterial infections than adults. But not only the susceptibility to infection is increased in neonates, but also their risk for developing post-inflammatory diseases such as bronchopulmonary dysplasia (BPD) and periventricular leukomalacia (PVL). This may be due to an impaired ability to terminate inflammation. In the study presented here, we aimed to investigate the proliferative response and the expression of immune-checkpoint molecules (ICM) and activation markers on neonatal T-cells in comparison to adult T-cells with the hypothesis that an increased activation of neonatal T-cells may contribute to the failure of inflammation resolution observed in neonates. We show that neonatal CD4+ and CD8+ T-cells show an increased proliferative capacity and an increased expression of activation markers compared to adult T-cells upon stimulation with OKT3 as well as a decreased expression of ICM, especially PD-L1 on their surface. This decreased expression of PD-L1 by neonatal T-cells was also observed after stimulation with GBS, but not after stimulation with E. coli, the two most important pathogens in neonatal sepsis. Expression of the T-cell receptor CD3 and the co-stimulatory molecule CD28 did not differ between adult and neonatal T-cells upon bacterial stimulation. Decreased expression of ICM upon T-cell activation may be a reason for the increased risk of neonates to develop post-inflammatory diseases.

Group B streptococci infection model shows decreased regulatory capacity of cord blood cells.

BACKGROUND: Sepsis is one of the leading causes of morbidity and mortality in the neonatal period. Compared to adults, neonates are more susceptible to infections, especially to systemic infections with Group B Streptococcus (GBS). Furthermore, neonates show defects in terminating inflammation. The immunological causes for the increased susceptibility to infection and the prolonged inflammatory response are still incompletely understood. METHODS: In the present study, we aimed to investigate the reaction of cord blood mononuclear cells (MNC) to stimulation with GBS in comparison to that of MNC from adult blood with focus on the proliferative response in an in vitro infection model with heat-inactivated GBS. RESULTS: We demonstrate that after stimulation with GBS the proliferation of T cells from adult blood strongly decreased, while the proliferation of cord blood T cells remained unchanged. This effect could be traced back to a transformation of adult monocytes, but not cord blood monocytes, to a suppressive phenotype with increased expression of the co-inhibitory molecule programmed death ligand 1 (PD-L1). CONCLUSIONS: These results point towards an increased inflammatory capacity of neonatal MNC after stimulation with GBS. Targeting the prolonged inflammatory response of neonatal immune cells may be a strategy to prevent complications of neonatal infections. IMPACT: Neonatal sepsis often leads to post-inflammatory complications. Causes for sustained inflammation in neonates are incompletely understood. We show that cord blood T cells exhibited increased proliferative capacity after stimulation with group B streptococci (GBS) in comparison to adult T cells. Adult monocytes but not cord blood monocytes acquired suppressive activity and expressed increased levels of PD-L1 after GBS stimulation. Increased proliferative capacity of neonatal T cells and decreased suppressive activity of neonatal monocytes during GBS infection may contribute to prolonged inflammation and development of post-inflammatory diseases in newborns.