CD8+ T cells are impaired during viral acute respiratory infection by coordinated inhibitory pathways

Abstract

My thesis project explores mechanisms controlling CD8+ T cell impairment in the lung during viral acute lower respiratory infection. I show that viral infection is required for lung T cell impairment and that cognate viral antigen recognized by the T cell receptor drives this process through the upregulation of inhibitory receptors. One such receptor, programmed death-1 (PD-1), is a key mediator of impairment during both primary infection and reinfection and prevents effective anti-viral immunity. Therapeutic blockade of the PD-1 pathway results in restored lung CD8+ T cell effector functions and enhances viral clearance without exacerbating lower airway pathology. Additionally, I show that PD-1 mediates CD8+ T cell dysfunction in a cell-intrinsic manner and further identify three additional inhibitory receptors that contribute to impairment. In particular, lymphocyte-activation gene 3 (LAG-3) rapidly compensates for loss of PD-1 signaling to return lung CD8+ T cells to an impaired state. In sum, I have elucidated mechanisms controlling lung CD8+ T cell impairment during viral acute lower respiratory infection, which have important implications for design of novel therapeutics and vaccine strategies against respiratory viruses.