PD-L1 is an intrinsic switch for natural killer cell-mediated, TRAIL-dependent antiviral function

Area of Science:

• Immunology
• Virology
• Respiratory Medicine

Background:

• Influenza A virus (IAV) causes significant global mortality, particularly in immunocompromised individuals.
• Existing IAV research predominantly uses healthy models, limiting understanding of pathogenesis in vulnerable populations.
• Immunocompromised patients exhibit distinct influenza disease progression, necessitating specific research models.

Purpose of the Study:

• To investigate natural killer (NK) cell activation and regulation during IAV infection in an immunocompromised model.
• To explore the therapeutic potential of targeting programmed death ligand 1 (PD-L1) in IAV infection.
• To elucidate the mechanisms underlying NK cell responses modulated by PD-L1 signaling.

Main Methods:

• Utilized recombination-activating gene 1 (Rag1)-knockout (KO) mice as a model of immunocompromised status.
• Administered a monoclonal antibody (mAb) targeting PD-L1 to IAV-infected Rag1-KO mice.
• Analyzed NK cell-intrinsic PD-L1 signaling, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression, and survival rates.

Main Results:

• PD-L1 blockade in IAV-challenged Rag1-KO mice triggered NK cell-intrinsic PD-L1 signaling.
• Treatment significantly delayed mortality in the immunocompromised mouse model.
• PD-L1 mAb treatment upregulated TRAIL on NK cells, which was essential for the observed therapeutic benefits.

Conclusions:

• PD-L1 signaling plays a critical role in regulating NK cell responses during IAV infection in immunocompromised hosts.
• Targeting PD-L1 represents a promising therapeutic strategy for influenza A virus infections in vulnerable populations.
• These findings offer a new perspective on innate immune responses to respiratory viruses and potential treatments.