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

Abstract

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-␣) 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-␣ production was 5 to 18 times higher in AB than in CB monocytes, whereas interleukin-1␣ (IL-1␣) stimulated similar levels of TNF-␣ 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-␣ 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-␣ 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-␣ response to LPS observed in immunologically naive newborns compared to the response in adults.

Type 1 IFN Induction by Cytosolic Nucleic Acid Is Intact in Neonatal Mononuclear Cells, Contrasting Starkly with Neonatal Hyporesponsiveness to TLR Ligation Due to Independence from Endosome-Mediated IRF3 Activation

“…Following isolation of mononuclear cells, we found no differences in leukocyte percentages and no differences in DC subsets between adult and cord blood. We also found that classical and inflammatory monocyte subsets are the same between cord and adult mononuclear cells, an observation previously reported in the literature (42,45,46) but in conflict with another report that suggested that decreased populations of monocytes could be responsible for observed hyporesponsiveness to LPS seen in neonates (41). Importantly, within our cohort, we found that monocytes isolated from either adult or neonate stimulated with CNA or TLR ligands mirrored the IFN response observed in the PBMC/CBMC system.…”

Dendritic Cells Differentiated from Human Umbilical Cord Blood-Derived Monocytes Exhibit Tolerogenic Characteristics

“…UCB contained a lower number of CD14 + CD16 + monocytes, which are known as activated monocytes, than APB. Concomitant with our findings, reduction of inflammatory CD14 + CD16 + monocytes in UCB and its implications for weak immune responses of newborns to infections has been demonstrated [21]. Here, we observed that PGE2 level in the UCB plasma has inverse correlation with the frequencies of CD14 + CD16 + cells.…”

“…UCB and APB exhibit difference in the ratio of CD14 + CD16 + monocytes to CD14 + CD16 -monocytes. UCB displays significantly reduced frequency in CD14 + CD16 + monocytes [21]. However, it is yet to be elucidated whether the lower proportions of CD14 + CD16 + monocytes in UCB have a correlation This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction.…”

Comparison of Human Neonatal and Adult Blood Leukocyte Subset Composition Phenotypes

“…In one previous study, monocyte subset frequencies as defined by CD14 and CD16 markers (classical monocytes-CD14++ CD16- and inflammatory monocytes-CD14+CD16+) were found to be similar in AB and CB [30] whereas another study reports inflammatory monocytes (CD14+ CD16+) to be lower in CB [31]. Both these papers do not mention patrolling monocytes.…”