Lack of Activation Marker Induction and Chemokine Receptor Switch in Human Neonatal Myeloid Dendritic Cells in Response to Human Respiratory Syncytial Virus

Abstract

Respiratory syncytial virus (RSV) causes disease early in life and can reinfect symptomatically throughout life without undergoing significant antigenic change. In contrast, reinfection by influenza A virus (IAV) requires antigenic change. The adaptive immune response depends on antigen presentation by dendritic cells (DC). We used myeloid DC (mDC) from cord blood and adult blood donors to evaluate whether immunological immaturity contributes to the inability to mount a fully protective immune response to RSV. While IAV induced some activation and chemokine receptor switching in cord blood mDC, RSV did not. This appeared to be due to a lack of activation and a weak and mostly reversible inhibition of DC functions. Both viruses induced a stronger activation of mDC from adults than mDC from cord blood. Thus, inefficient stimulation of mDC by RSV and immunological immaturity may contribute to reduced immune responses and increased susceptibility to RSV disease and reinfection in young infants. ABSTRACT Respiratory syncytial virus (RSV) infects and causes disease in infants and reinfects with reduced disease throughout life without significant antigenic change. In contrast, reinfection by influenza A virus (IAV) largely requires antigenic change. The adaptive immune response depends on antigen presentation by dendritic cells (DC), which may be too immature in young infants to induce a fully protective immune response against RSV reinfections. We therefore compared the ability of RSV and IAV to activate primary human cord blood (CB) and adult blood (AB) myeloid DC (mDC). While RSV and IAV infected with similar efficiencies, RSV poorly induced maturation and cytokine production in CB and AB mDC. This difference between RSV and IAV was more profound in CB mDC. While IAV activated CB mDC to some extent, RSV did not induce CB mDC to increase the maturation markers CD38 and CD86 or CCR7, which directs DC migration to lymphatic tissue. Low CCR7 surface expression was associated with high expression of CCR5, which keeps DC in inflamed peripheral tissues. To evaluate a possible inhibition by RSV, we subjected RSV-inoculated AB mDC to secondary IAV inoculation. While RSV-inoculated AB mDC responded to secondary IAV inoculation by efficiently upregulating activation markers and cytokine production, IAV-induced CCR5 downregulation was slightly inhibited in cells exhibiting robust RSV infection. Thus, suboptimal stimulation and weak and mostly reversible inhibition seem to be responsible for inefficient mDC activation by RSV. The inefficient mDC stimulation and immunological immaturity in young infants may contribute to reduced immune responses and incomplete protection against RSV reinfection. IMPORTANCE Respiratory syncytial virus (RSV) causes disease early in life and can reinfect symptomatically throughout life without undergoing significant antigenic change. In contrast, reinfection by influenza A virus (IAV) requires antigenic change. The adaptive immune response depends on antigen presentation by dendritic cells (DC). We used myeloid DC (mDC) from cord blood and adult blood donors to evaluate whether immunological immaturity contributes to the inability to mount a fully protective immune response to RSV. While IAV induced some activation and chemokine receptor switching in cord blood mDC, RSV did not. This appeared to be due to a lack of activation and a weak and mostly reversible inhibition of DC functions. Both viruses induced a stronger activation of mDC from adults than mDC from cord blood. Thus, inefficient stimulation of mDC by RSV and immunological immaturity may contribute to reduced immune responses and increased susceptibility to RSV disease and reinfection in young infants.