Document Type
Article
Publication Date
2-24-2026
Original Citation
Frank K,
Sharma H,
Motakis E,
Nourbakhsh N,
Abeynaike S,
Huynh T,
Jones C,
Johnson S,
Tompkins S,
Paust S.
PD-L1 is an intrinsic switch for natural killer cell-mediated, TRAIL-dependent antiviral function. Cell Rep. 2026;45(2):116939.
Keywords
JGM, SS1
JAX Source
Cell Rep. 2026;45(2):116939.
ISSN
2211-1247
PMID
41615805
DOI
https://doi.org/10.1016/j.celrep.2026.116939
Grant
This work was supported by the National Institutes of Health and the National Institute of Allergy and Infectious Diseases (R01 AI174590 to S.P.) and unrestricted funds from the Scripps Research Institute, La Jolla, CA (to S.P.).
Abstract
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.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.