Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

Reduced frequency of high TLR4-expressing CD14+ CD16+ monocyte subset in cord compared to adult blood contributes to LPS hyporesponsiveness in newborns

Abstract

The human innate immune response to pathogens is not fully effective and mature until well into childhood, as exemplified by varying responses to TLR agonists in newborns compared to adults. To better understand the mechanistic basis for this age-related difference in innate immunity we compared TNFα production by monocytes from cord blood (CB) and adult blood (AB) in response to LAM (lipoarabinomannan from M. tuberculosis, TLR2 ligand) and LPS (lipopolysaccharide from E. coli, TLR4 ligand). LPS or LAM-induced TNFα production was 5-18 times higher in adult compared to CB monocytes, whereas IL-1α stimulated similar levels of TNFα in both groups, suggesting that decreased responses to LPS or LAM in CB are unlikely 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 TNFα production. Importantly, the frequency of CD14+ CD16+ monocytes in CB was 2.5-fold lower compared to 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 TNFα in response to LPS (p=0.004) compared to CB from unsensitized Kenyan or North American newborns. Thus, a reduced CD14+CD16+ activated/differentiated monocyte subset and a correspondingly lower functional TLR4 on monocytes contributes to the relatively low TNFα response to LPS observed in immunologically naïve newborns when compared to adults.