RT Journal Article
SR Electronic
T1 The specific features of the developing T cell compartment of the neonatal lung are a determinant of respiratory syncytial virus immunopathogenesis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.08.14.250829
DO 10.1101/2020.08.14.250829
A1 Démoulins, Thomas
A1 Brügger, Melanie
A1 Zumkehr, Beatrice
A1 Oliveira Esteves, Blandina I.
A1 Mehinagic, Kemal
A1 Fahmi, Amal
A1 Borcard, Loïc
A1 Taddeo, Adriano
A1 Posthaus, Horst
A1 Benarafa, Charaf
A1 Ruggli, Nicolas
A1 Alves, Marco P.
YR 2020
UL http://biorxiv.org/content/early/2020/10/23/2020.08.14.250829.abstract
AB The human respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections in infants, possibly due to the specific features of the immature neonatal pulmonary immune system. Using the newborn lamb, a classical model of human lung development and a state-of-the-art 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.AUTHOR SUMMARY By using a state-of-the-art translational model with full accessibility to the small airways at defined early life periods, we provide an unpreceded characterization of the developing T cell compartment in the distal lungs of healthy and RSV-infected neonates. This process is highly dynamic and tightly regulated, characterized by colonizing T-cell subsets that synergize towards a narrow pro-tolerogenic immunological window. We believe our work constitutes a solid basis to clarify the age dependency of RSV immunopathogenesis, and should be considered in vaccine design, which remains challenging after five decades of effort.Competing Interest StatementThe authors have declared no competing interest.