Severely depressed interleukin-17 production by human neonatal mononuclear cells

Abstract

Background:The role of T-helper 17 cells (Th17) in neonatal host defense remains to be fully elucidated. Interleukin (IL)-17 plays an important role in the immune response to bacterial and fungal pathogens by promoting inflammation. Methods: We examined neonatal production of IL-17 in mixed mononuclear cells (MMCs) isolated from umbilical cord blood for comparison with adult peripheral blood mononuclear cell controls. results: IL-17 production was profoundly diminished in MMCs isolated from cord blood when compared with MMCs from adult blood. This was associated with a marked reduction in the population of CCR6 + IL-17 + T-cells in the neonatal cord blood. We also found diminished intracellular formation of IL-17, and diminished IL-17 responses to both group B streptococci (GBS) and Escherichia coli. Neonatal mononuclear cells were found to adequately phosphorylate signal transducer and activator of transcription 3, pY705, and pS727. We and others have reported markedly reduced interferon-γ production by neonate mononuclear cells exposed to GBS. Here, we correct that profound abnormality with added IL-17. conclusion: Our results suggest that profound deficiency of IL-17 production associated with a marked decrease in Th17 cells likely contributes significantly to the increased susceptibility of human neonates to invasive bacterial and fungal infections.

Antifungal Immunological Defenses in Newborns

“…Adults with genetic mutations impairing RORC or STAT3 function have increased susceptibility to chronic mucocutaneous candidiasis due to diminished Th17 function (97, 98). STAT3 phosphorylation occurs in neonatal T cells although whether reduced expression may limit Th17 differentiation in this age group is unclear (99). Neonatal T lymphocytes also have a reduced ability to differentiate into interferon-γ-producing CD4 lymphocytes (5), which play a role protecting against fungi, through the activation of other cellular immune components (e.g., phagocytes) (9).…”

IL‐17 in neonatal health and disease

“…Increased concentrations of IL-17A during early inflammatory conditions enables Th17 cells to assume Th1-like effector functions, thereby expediting the recruitment of stimulated neutrophils to the site of infection and activating of regional macrophages to promote pathogen clearance 20, 38, 39 . In the most extreme preterm neonates, however, clinically relevant deficiencies of Th17 and Th1 cellular responses, due to impaired induction of the p40 subunit common to IL-12 and IL-23, leads to decreased concentrations of these interleukins 21,40,41 . Reductions in IL-12 and IL-23 in this vulnerable patient population can heighten risks of early onset neonatal sepsis despite the presence of higher concentrations of other pro-inflammatory cytokines 21,41 .…”

“…In general, IL-17A is important in combating extracellular pathogens including Gram-positive, Gram-negative, and fungal microbes 40,66,67 . Neonates demonstrate reduced baseline production of IL-17A compared to adults, which may diminish neonatal immune responses and contribute to their increased susceptibility to infection by group B Streptococcus , Escherichia coli 40 , and Klebsiella pneumoniae 20,68 .…”

“…Neonates demonstrate reduced baseline production of IL-17A compared to adults, which may diminish neonatal immune responses and contribute to their increased susceptibility to infection by group B Streptococcus , Escherichia coli 40 , and Klebsiella pneumoniae 20,68 . Because IL-17A levels are similar between preterm and term neonates, its production is not dependent upon immune maturation or advancing gestational age 20 .…”

Chorioamnionitis, IL‐17A, and fetal origins of neurologic disease

“…The cytokine IL-17A is an important component of early host immune responses that target and eliminate extracellular pathogens including Gram-positive, Gram-negative, and fungal microbes 62–64 . Neonates demonstrate reduced baseline production of IL-17A compared to adults, which may diminish their ability to generate proinflammatory immune responses and increase their susceptibility to infection by group B Streptococcus, Escherichia coli 53 , and Klebsiella pneumoniae 24, 65 .…”