The specific features of the developing T cell compartment of the neonatal lung are a determinant of respiratory syncytial virus immunopathogenesis

Abstract

The human respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections in infants, possibly due to the properties of the immature neonatal pulmonary immune system. Using the newborn lamb, a classical model of human lung development and a translational model of RSV infection, we aimed to explore the role of cell-mediated immunity in RSV disease during early life. Remarkably, in healthy conditions, the developing T cell compartment of the neonatal lung showed major differences to that seen in the mature adult lung. The most striking observation being a high baseline frequency of bronchoalveolar IL-4-producing CD4 and CD8 T cells, which declined progressively over developmental age. RSV infection exacerbated this pro-type 2 environment in the bronchoalveolar space, rather than inducing a type 2 response per se. Moreover, regulatory T cell suppressive functions occurred very early to dampen this pro-type 2 environment, rather than shutting them down afterwards, while γδ T cells dropped and failed to produce IL-17. Importantly, RSV disease severity was related to the magnitude of those unconventional bronchoalveolar T cell responses. These findings provide novel insights in the mechanisms of RSV immunopathogenesis in early life, and constitute a major step for the understanding of RSV disease severity.

Neonatal Immune Responses to Respiratory Viruses

“…Compared to adult mice, the CD4 + T cell compartment of neonatal mice showed increased proliferative capacity, expression of IL-4Rα, and differentiation into Th2 cells following RSV infection ( 172 ). Using a lamb model, neonatal RSV infection further increased Th2 cytokine production in the setting of an elevated baseline Th2 milieu ( 173 ). This skewing towards type 2 inflammation (e.g.…”

Multiparameter flow cytometry assay to analyze the pulmonary T cell profiles in the ovine model of respiratory syncytial virus infection

“… Timing: 48–72 h depending on HEp-2 cell confluence and cytopathic effect Note: To modulate respiratory syncytial virus (RSV) disease severity in neonatal lambs, we used two different strains, namely RSV-ON1-H1 and RSV A2 ( Démoulins et al., 2021 ). RSV-ON1-H1 was the major genotype circulating in central Europe during the RSV seasons of 2012–2017, whereas RSV A2 is a well characterized prototypical strain of RSV.…”

“…In accordance with the principles of the 3Rs, suckling lambs were held together with their mothers and fed ad libitum . For further details on the procedures associated with gestation and group allocation, please refer to ( Démoulins et al., 2021 ). Screening for the initial presence of RSV-specific neutralizing antibodies was done for all ewes.…”

“…We then describe tissue isolation and preparation of cell suspensions, followed by FCM acquisition to identify different T cell subsets. For complete details on the use and execution of this protocol, please refer to Démoulins et al. (2021) .…”

“…For complete details on the use and execution of this protocol, please refer to Démoulins et al. (2021) .…”