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.
Highlights
The human respiratory syncytial virus (RSV) is a seasonal virus, known as the major cause of lower respiratory tract infection during early childhood [1,2]
By using a translational model with full accessibility to the small airways at defined early life periods, we provide a characterization of the developing T cell compartment in the distal lungs of healthy and RSV-infected neonates
RSV A2 proved to replicate in ovine well-differentiated airway epithelial cell (WD-AEC) cultures, with a peak of infectious release at 72–96 h, as shown in S1A Fig. to monitor the immune responses during the acute, recovery and convalescence phases of RSV disease, time-points were selected as follow: 3 and 6 days post-infection (p.i.), to evaluate the innate and early adaptive responses; 14 days p.i. to assess the adaptive mechanisms and virus clearance; 42 days p.i. to investigate the impact of RSV A2 infection on the immune cell colonization of the developing lung
Summary
The human respiratory syncytial virus (RSV) is a seasonal virus, known as the major cause of lower respiratory tract infection during early childhood [1,2]. There are risk factors for RSV severity such as prematurity and congenital heart disease, the majority of hospitalized infants are previously healthy [4,5,6,7], suggesting that the disease is partially linked to inherent properties of early life immunity. The first exposure to pathogens occurs during the early postnatal period and is critical for lung colonization by immune cells. Neonates have a higher frequency of T cells that differentiate into regulatory T cells (Tregs) compared to adults, to facilitate self-tolerance to developing organs [10]. The developing lung is characterized by a type 2 immune phenotype, and the pulmonary T cell responses present a T helper type 2 (Th2) bias [11,12]. Neonatal γδ T cells, a T cell subset enriched at mucosal barrier sites, have an impaired capacity to respond to stimulation [13,14,15,16]
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