The role of type I regulatory cells in regulating immune responses to influenza infection

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.