Pulmonary Microvascular Endothelial Antigen Presentation Activates Resident CD8⁺ T Cells to Restrain Influenza Lung Injury

The remaining unacceptably high mortality of influenza-induced acute respiratory distress syndrome underscores the urgent need to identify key cellular drivers of host responses. Endothelial cells (ECs) are increasingly recognized for their immunomodulatory roles, but whether they function as antigen-presenting cells (APCs) following respiratory viral infection remains unknown. Here, we show that influenza A virus H1N1 restrictively infects pulmonary microvascular ECs (PMVECs) during late-stage acute lung injury, triggering robust MHC class I (MHC-I) upregulation in vitro, in vivo, and in ex vivo human precision-cut lung slices. Infected PMVECs present H1N1 antigens via MHC-I and co-stimulatory CD40 to lung-resident CD8⁺ T cells, driving their proliferation and effector function (Granzyme B, IFNγ) to promote viral clearance and resolve inflammation. This process is IFNγ-dependent and STAT1-regulated, forming a positive feedback loop that enhances PMVEC antigen presentation and CD8⁺ T cells activation. By contrast, the emerging H5N1 (A/Texas/37/2024) infect pulmonary ECs earlier and more broadly but elicits weaker pulmonary EC-driven CD8 + T cell responses, potentially contributing to its higher pathogenicity. These findings reveal PMVECs as active APCs in antiviral defense and highlight new avenues for immunotherapeutic intervention.