Acquisition of Adult-Like TLR4 and TLR9 Responses during the First Year of Life

Abstract

BackgroundCharacteristics of the human neonatal immune system are thought to be responsible for heightened susceptibility to infectious pathogens and poor responses to vaccine antigens. Using cord blood as a source of immune cells, many reports indicate that the response of neonatal monocytes and dendritic cells (DC) to Toll-like receptor (TLR) agonists differs significantly from that of adult cells. Herein, we analyzed the evolution of these responses within the first year of life.Methodology/Principal FindingsBlood samples from children (0, 3, 6, 9, 12 month old) and healthy adults were stimulated ex vivo with bacterial lipopolysaccharide (LPS, TLR4 agonist) or CpG oligonucleotides (TLR9 agonist). We determined phenotypic maturation of monocytes, myeloid (m) and plasmacytoid (p) DC and production of cytokines in the culture supernatants. We observed that surface expression of CD80 and HLA-DR reaches adult levels within the first 3 months of life for mDCs and 6–9 months of life for monocytes and pDCs. In response to LPS, production of TNF-α, IP-10 and IL-12p70 reached adult levels between 6–9 months of life. In response to CpG stimulation, production of type I IFN-dependent chemokines (IP-10 and CXCL9) gradually increased with age but was still limited in 1-year old infants as compared to adult controls. Finally, cord blood samples stimulated with CpG ODN produced large amounts of IL-6, IL-8, IL-1β and IL-10, a situation that was not observed for 3 month-old infants.ConclusionsThe first year of life represents a critical period during which adult-like levels of TLR responses are reached for most but not all cytokine responses.

Malaria Modifies Neonatal and Early-Life Toll-Like Receptor Cytokine Responses

“…Nevertheless, and as seen both in Caucasian (47,48) and Gambian infants (28), we did find that R848 was the agonist that consistently induced the strongest proand anti-inflammatory cytokine responses in Beninese infants, while responses induced by the TLR9 agonist were relatively weak. Cytokine production in response to the TLR9 agonist nevertheless increased from birth up to 6 months of age, a pattern not seen in the comparable studies of European or African infants (28,49). These disparate findings may be explained (i) by the comparatively broad target populations of R848 that can stimulate pDC, mDC, monocytes, and B cells (50) and (ii) by the TLR9 ligand we used (ODN CpG 2216) that exerts selective activity only on pDC (46) as opposed to on both pDC and B cells (28,49).…”

“…Cytokine production in response to the TLR9 agonist nevertheless increased from birth up to 6 months of age, a pattern not seen in the comparable studies of European or African infants (28,49). These disparate findings may be explained (i) by the comparatively broad target populations of R848 that can stimulate pDC, mDC, monocytes, and B cells (50) and (ii) by the TLR9 ligand we used (ODN CpG 2216) that exerts selective activity only on pDC (46) as opposed to on both pDC and B cells (28,49). Our data also confirm published observations of a decrease in the production of IL-10 in response to TLR4 agonists postnatally (29).…”

The Pioneer Gut Microbiota in Human Neonates Vaginally Born at Term—A Pilot Study

“…Gram-negative bacteria have lipopolysaccharides with strong proinflammatory capacity in the outer part of the cell wall, thereby contributing to a subclinical inflammatory tone connected to a range of metabolic disorders such as obesity and type 2 diabetes (12). Noteworthy, in neonates with a not yet fully mature immune system, lipopolysaccharide stimulation have different effects compared with adult individuals (13). Various reports show transfer of the maternal vaginal microbiota to the newborn (14,15), highlighting the importance of a healthy vaginal microbiota for desirable stimulation of the neonatal immune system.…”

Childhood Acute Leukemias in Hispanic Population: Differences by Age Peak and Immunophenotype

“…Some properties in hematopoietic development, including cell-cycle progression, transcription-factor networks, and growth-factor production, show substantial differences between newborns and adults (Mayani, 2010;Nguyen et al, 2010;Pelayo et al, 2006b). During fetal and neonatal development, the hematopoietic system faces a complex set of demands, including rapid population turnover, protection against infection, and avoidance of harmful inflammatory immune responses (Levy, 2007;Pelayo et al, 2006b).…”