Staphylococcus aureusconvert neonatal conventionalCD4⁺Tcells intoFOXP3⁺ CD25⁺ CD127^lowTcells via thePD‐1/PD‐L1 axis

Abstract

The gut microbiota provides an important stimulus for the induction of regulatory T (Treg) cells in mice, whether this applies to newborn children is unknown. In Swedish children, Staphylococcus aureus has become a common early colonizer of the gut. Here, we sought to study the effects of bacterial stimulation on neonatal CD4+ T cells for the induction of CD25+ CD127low Treg cells in vitro. The proportion of circulating CD25+ CD127low Treg cells and their expression of FOXP3, Helios and CTLA-4 was examined in newborns and adults. To evaluate if commensal gut bacteria could induce Treg cells, CellTrace violet-stained non-Treg cells from cord or peripheral blood from adults were co-cultured with autologous CD25+ CD127low Treg cells and remaining mononuclear cells and stimulated with S. aureus. Newborns had a significantly lower proportion of CD25+ CD127low Treg cells than adults, but these cells were Helios+ and CTLA-4+ to a higher extent than in adults. FOXP3+ CD25+ CD127low T cells were induced mainly in neonatal CellTrace-stained non-Treg cells after stimulation with S. aureus. In cell cultures from adults, S. aureus induced CD25+ CD127low T cells only if sorted naive CD45RA+ non-Treg cells were used, but these cells expressed less FOXP3 than those induced from newborns. Sorted neonatal CD25+ CD127low T cells from S. aureus-stimulated cultures were still suppressive. Finally, blocking PD-L1 during stimulation reduced the induction of FOXP3+ CD25+ CD127low T cells. These results suggest that newborns have a higher proportion of circulating thymically derived Helios+ Treg cells than adults and that S. aureus possess an ability to convert neonatal conventional CD4+ T cells into FOXP3+ CD25+ CD127low Treg cells via the PD-1/PD-L1 axis.

FOXP3+Helios+ Regulatory T Cells, Immune Activation, and Advancing Disease in HIV-Infected Children

“…In our cohort of HIV negative-unexposed children from Kenya, the FOXP3+Helios+ subset identified markedly more Tregs than FOXP3 and CD25 coexpression. Approximately 75% of FOXP3+CD25+ Tregs were Helios+, a level consistent with our previous study of healthy and HIV+ adults and other reports in healthy adults, neonates, and vertically infected HIV+ children in the United States 14,15,17,23 . Importantly, the traditional Treg phenotype of FOXP3+CD25+ cells underestimated the proportion of Tregs in HIV+ children considerably more than in HIV- children.…”

“…Interestingly, in a study of infants, Rabe et al . revealed neonates express higher levels of Helios in Tregs compared to adults 17 . Very few reports examine Tregs in HIV infected children, in whom a disruption may have the added consequence of altering responses to essential childhood vaccines.…”

Significant augmentation of regulatory T cell numbers occurs during the early neonatal period

“…Various factors have the potential to modulate the ontogenic development of T regs . Such factors in neonates include gestational age, intestinal microbiota, Toll‐like receptor (TLR)‐2 polymorphisms and IL‐10 polymorphisms, while the maternal factors include smoking in pregnancy, allergic disease and chorioamnionitis . A negative correlation between gestational age and T reg cell development shown in this study using CB was consistent with previous reports.…”

Alum impairs tolerogenic properties induced by allergoid‐mannan conjugates inhibiting mTOR and metabolic reprogramming in human DCs

“…Here, we performed a comprehensive immunologic study of the potential influence of alum in the tolerogenic effects imprinted by PM targeting CLRs in DCs . Alum significantly decreases the production of IL‐10 and PD‐L1 expression in human PM‐activated DCs, which are molecules involved in the generation of functional Treg cells . In contrast, the OX40‐L expression, a molecule favouring Th2 polarization, is significantly increased in the presence of alum.…”