Each year, influenza A virus (IAV) infection of the lung causes half a million deaths worldwide. Patients with compromised immunity experience distinct influenza pathogenesis; however, most IAV-related research is done with wild-type mice or people who are otherwise healthy. We utilize a model of immunocompromised recombination-activating gene 1 (Rag1)-knockout (KO) mice to discover natural killer (NK) cell activation and regulation mechanisms during IAV infection. The treatment of IAV-challenged Rag1-KO mice with a monoclonal antibody (mAb) targeting programmed death ligand 1 (PD-L1) triggers NK cell-intrinsic signaling of PD-L1 and significantly delays lethality. This treatment upregulates tumor necrosis factor-related apoptosis-inducing ligand on NK cells downstream of PD-L1 signaling and is required for the benefits of PD-L1 mAb treatment in IAV-challenged Rag1-KO mice. These results present a paradigm shift for understanding the innate immune response to respiratory virus infections, offering an alternative approach for therapeutic treatment of IAV infections in patients with compromised immunity.
Frank et al. (Thu,) studied this question.