Ontogeny of Toll-Like Receptor Mediated Cytokine Responses of Human Blood Mononuclear Cells

TLDR

Newborns and young infants experience the highest infectious morbidity and mortality, which decline over the first years of life, and most vaccines are not given at birth. The study aims to deepen understanding of immune system development during the first two years of life. The authors performed a longitudinal cohort study of 35 subjects, comprehensively analyzing innate immune responses to TLR stimulation over the first two years of life. Innate TLR responses varied with age: IL‑23 and IL‑6 peaked at birth then fell over two years before rising again in adulthood; IFN‑α reached adult levels by one year; IL‑12p70 and IFN‑γ rose slowly but remained below adult levels at two years; IL‑10 production declined from a birth peak to adult levels by one or two years; TNF‑α and IL‑1β responses differed by stimulus; these findings refute a simple linear maturation model and reveal age‑specific qualitative and quantitative shifts in innate immunity.

Abstract

Newborns and young infants suffer increased infectious morbidity and mortality as compared to older children and adults. Morbidity and mortality due to infection are highest during the first weeks of life, decreasing over several years. Furthermore, most vaccines are not administered around birth, but over the first few years of life. A more complete understanding of the ontogeny of the immune system over the first years of life is thus urgently needed. Here, we applied the most comprehensive analysis focused on the innate immune response following TLR stimulation over the first 2 years of life in the largest such longitudinal cohort studied to-date (35 subjects). We found that innate TLR responses (i) known to support Th17 adaptive immune responses (IL-23, IL-6) peaked around birth and declined over the following 2 years only to increase again by adulthood; (ii) potentially supporting antiviral defense (IFN-α) reached adult level function by 1 year of age; (iii) known to support Th1 type immunity (IL-12p70, IFN-γ) slowly rose from a low at birth but remained far below adult responses even at 2 years of age; (iv) inducing IL-10 production steadily declined from a high around birth to adult levels by 1 or 2 years of age, and; (v) leading to production of TNF-α or IL-1β varied by stimuli. Our data contradict the notion of a linear progression from an 'immature' neonatal to a 'mature' adult pattern, but instead indicate the existence of qualitative and quantitative age-specific changes in innate immune reactivity in response to TLR stimulation.