Reduced Frequency of a CD14+ CD16+ Monocyte Subset with High Toll-Like Receptor 4 Expression in Cord Blood Compared to Adult Blood Contributes to Lipopolysaccharide Hyporesponsiveness in Newborns

The human innate immune response to pathogens is not fully effective and mature until well into childhood, as exemplified by various responses to Toll-like receptor (TLR) agonists in newborns compared to adults. To better understand the mechanistic basis for this age-related difference in innate immunity, we compared tumor necrosis factor alpha (TNF-alpha) production by monocytes from cord blood (CB) and adult blood (AB) in response to LAM (lipoarabinomannan from Mycobacterium tuberculosis, a TLR2 ligand) and LPS (lipopolysaccharide from Escherichia coli, a TLR4 ligand). LPS or LAM-induced TNF-alpha production was 5 to 18 times higher in AB than in CB monocytes, whereas interleukin-1 alpha (IL-1 alpha) stimulated similar levels of TNF-alpha in both groups, suggesting that decreased responses to LPS or LAM in CB are unlikely to be due to differences in the MyD88-dependent signaling pathway. This impaired signaling was attributable, in part, to lower functional TLR4 expression, especially on CD14(+) CD16(+) monocytes, which are the primary cell subset for LPS-induced TNF-alpha production. Importantly, the frequency of CD14(+) CD16(+) monocytes in CB was 2.5-fold lower than in AB (P< 0.01). CB from Kenyan newborns sensitized to parasite antigens in utero had more CD14(+) CD16(+) monocytes (P = 0.02) and produced higher levels of TNF-alpha in response to LPS (P = 0.004) than CB from unsensitized Kenyan or North American newborns. Thus, a reduced CD14(+) CD16(+) activated/differentiated monocyte subset and a correspondingly lower level of functional TLR4 on monocytes contributes to the relatively low TNF-alpha response to LPS observed in immunologically naive newborns compared to the response in adults.