Immune regulation and evasion of acute respiratory virus infection

Abstract

Viral respiratory infections, including infection by human metapneumovirus (HMPV), are associated with T cell impairment, wherein CD8+ T cells exhibit diminished production of cytokines and cytotoxic molecules. In this thesis I show that CD4+ regulatory T cells (Tregs) contribute to decreased CD8+ T cell function and impair clearance of HMPV. Additionally, I demonstrate a temporal role of Tregs in respiratory virus infection, where Tregs are essential during immune priming to promote cell migration and to control the balance of type 1 and type 2 immunity. In this work, I also explored the role of the inhibitory ligand PD-L1 in T cell impairment. PD-L1 is the primary ligand that for the inhibitory receptor PD-1, and antibody blockade of PD-L1 restored CD8+ T cell function in T cell impairment. I found that paradoxically, however, mice genetically deficient in PD-L1 have even further reduced T cell function and antiviral immunity during respiratory virus infection. Finally, I investigated the host species permissiveness of HMPV and found that this is limited by the virus’ capacity to antagonize the interferon signaling pathway of primates and mice.