TGFβ-PDL1 signaling in neutrophils preserves lung barrier during hyperinflammation.

Summary

A TGFβ–PD‑L1 axis in neutrophils functions as an immune checkpoint that limits pathogenic hyperactivation during cytokine storm, preserving lung barrier integrity while maintaining host defense. Neutrophil-specific PD‑L1 deletion disrupted intravascular clustering and exacerbated tissue infiltration, but restored trafficking to infection foci.

Key Findings

• TGFβ signaling upregulates PD‑L1 on neutrophils and modulates activation during hyperinflammatory states.
• Disrupting TGFβ signaling restored neutrophil migration but caused excessive activation, severe pulmonary damage, and increased spontaneous lung bacterial infection.
• Neutrophil PD‑L1 promoted intravascular clustering and limited tissue infiltration; neutrophil-specific PD‑L1 deletion reversed clustering and altered trafficking.

Clinical Implications

Targeting the TGFβ–PD‑L1 axis on neutrophils may enable precision control of hyperinflammation without compromising antimicrobial defense, informing future therapeutic strategies in sepsis and acute lung injury.

Limitations

• Findings are in murine models; human validation and translational dosing windows are unknown
• Potential trade-offs between barrier protection and antimicrobial trafficking require careful balancing in therapy

Future Directions

Validate the TGFβ–PD‑L1 axis in human sepsis cohorts and lung tissues; explore pharmacologic modulation of neutrophil PD‑L1; define therapeutic windows that optimize defense and limit injury.