The role of type I regulatory cells in regulating immune responses to influenza infection
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(Thesis)
Date
2022
Authors
Abbott, Caitlin
Editors
Advisors
McColl, Shaun
Comerford, Iain
Comerford, Iain
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Abstract
The resolution of influenza A virus (IAV) infection requires T cell-dependent immune
regulation. In severe cases, without appropriate control of the immune response,
the inflammation resulting from respiratory viral infection can lead to pneumonia and
death. It is known that regulatory T cells are important for many aspects of immune
regulation including preventing uncontrolled inflammation and limiting tissue damage.
The quintessential and most studied regulatory T cell is the FOXP3+ Treg. Type I regulatory
(Tr1) cells are also known to be present in different infection settings but are
far less understood. Tr1 cells are defined as IL-10+ FOXP3- CD4+ T cells, enriched for
co-inhibitory molecule expression, and capable of suppressing effector T cell responses.
In the present study Tr1-like cells accumulated in the parenchyma of the IAV-infected
lungs at day 7 post infection where they represented the dominant source of T cell-derived
IL-10. IAV infection of a known model of Tr1 deficiency (Il27ra-/- mice) resulted in
increased weight loss and delayed recovery from maximum infection-induced weight loss.
Adoptive transfer of in vitro-derived polyclonal Tr1 cells into Il27ra-/- mice led to Tr1
cell recruitment to the lungs and significantly improved recovery from infection-induced
weight loss. This established a role for Tr1 cells in the resolution of inflammation in IAV
infection. Detailed investigation found four distinct bona fide Tr1 cell populations based
on expression of the surface molecules LAG-3 and CD49b. Although all four populations
were suppressive, however, only CD49b-expressing Tr1 cells exhibited IL-10-dependent
suppression of effector T cell division. These results determined that Tr1 populations
from the IAV-infected lungs exhibited differences in kinetics of accumulation, localisation,
suppressive capacity, mechanism of suppression, and molecular profile. Overall, this study
points toward a role for Tr1 cells in the resolution of inflammation in IAV infection.
School/Discipline
School of Molecular and Biological Sciences
Dissertation Note
Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biological Sciences, 2022
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