Tc17-driven antibody-independent mucosal immunity is critical for protection against extracellular bacterial pneumonia

Abstract

Klebsiella pneumoniae (Kp) is a WHO high-priority pathogen for vaccine development, yet previous efforts failed largely because key protective immune mechanisms remain unclear. Here we show that protective immunity conferred by mucosal mRNA vaccines (but not parenteral) require neither serum IgG nor airway secretory IgA, but instead depends on a previously unrecognized lung-resident CD8IL-17 T-cells (Tc17) that rapidly recruits neutrophils/macrophages to eliminate bacteria. To therapeutically harness this paradigm, we developed INSPIRE, a machine learning-engineered exosome platform incorporating donor-screened, miRNA-bioactive backbones (miR-21-mediated airway barrier penetration and miR-155-associated dendritic-cell activation through SOCS1/Inpp5d axis) and computationally designed peptides that boosts 11.6-fold mRNA encapsulation and 3-fold dendritic-cell cross-presentation. Intranasal INSPIRE-mRNA vaccination confers near-complete protection against clinically relevant Kp strains while intramuscular counterparts fail (below ~30% survival). Leveraging pIgR-/- and IL-17-/- mice coupled with T-cell depletions, we demonstrate the protection is Tc17-dependent. This work overturns the antibody-centric dogma and redefines a non-canonical Tc17-correlate for extracellular bacterial pneumonia.