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

Klebsiella pneumoniae (Kp) is a highly significant pathogen, posing a major threat due to the lack of effective vaccines. Previous attempts to develop a vaccine have failed due to the unclear mechanisms behind immunity. The researchers discovered that protection against Kp in the lungs is not dependent on the presence of serum IgG or secretory IgA found in the airways. Instead, it relies on a novel type of T-cells, known as CD8IL-17 T-cells (Tc17), which swiftly recruit neutrophils and macrophages to combat the bacteria.

To leverage this new understanding, the scientists developed INSPIRE – a machine learning-engineered exosome platform. This platform incorporates donor-screened miRNA-bioactive backbones, boosting mRNA encapsulation by a factor of 11.6, and dendritic-cell cross-presentation by three times. This enhancement is achieved through computational design of peptides and the activation of dendritic cells via the SOCS1/Inpp5d axis.

When administered intranasally, INSPIRE-mRNA vaccination showed near-complete protection against clinically relevant Kp strains, while the intramuscular versions fell short of providing adequate protection, with survival rates dropping below 30%. By analyzing pIgR-/- and IL-17-/- mice, along with T-cell depletions, the researchers confirmed that the protection is indeed dependent on Tc17.

This groundbreaking study challenges the long-standing belief in antibody-centric immunity and introduces a new non-canonical correlate for protection against extracellular bacterial pneumonia, attributed to Tc17 cells.