Infection of nonclassic monocytes by respiratory syncytial virus induces an imbalance in the CD4 ⁺ T-cell subset response

Respiratory syncytial virus (RSV) causes lower respiratory tract infections in infants and young children, leading to a pathogenesis-associated imbalance in CD4⁺ T-cell subsets and monocyte subsets. To investigate whether RSV affects the imbalance of CD4⁺ T-cells through monocytes, we examined the effects of the RSV-infected monocyte subset on CD4⁺ T-cell subsets, namely, Th1, Th2, Th17, and regulatory T (Treg) subsets, on proliferation <i>in vitro</i> and identified key monocyte-derived cytokines. We found that RSV efficiently infects CD16⁺ monocytes, but not CD16^- monocytes, <i>via</i> cocultures of CD4⁺ T-cells with RSV-infected CD16⁺ monocytes, inhibits Treg cell proliferation and increases Th2 cell frequency, suggesting that RSV causes an imbalance in the CD4⁺ T-cell subset by primarily infecting CD16⁺ monocytes. Our data also revealed that IL-1β and IL-10 are key cytokines responsible for the activities of RSV-infected CD16⁺ monocytes. In a mouse model, we found that high-efficiency RSV infection of mouse Ly6C^- monocytes, corresponding to CD16⁺ monocytes in humans, and adoptive transfer of Ly6C^- monocytes during RSV infection decreased the Treg frequency in the lungs and aggravated pneumonia. Our data indicate that RSV can increase its pathogenesis through infection of nonclassic monocytes, leading to a CD4⁺ T-cell imbalance.IMPORTANCEThis study identified a pathogenesis pathway related to the RSV-nonclassic monocyte-IL-1β/IL-10-CD4⁺ T-cell subset balance, which links the heterogeneity of monocytes to RSV pathogenesis and elucidates a new mechanism by which RSV infection disrupts the balance of CD4⁺ T cells during RSV infection. These new findings provide potential therapeutic targets for RSV infection.