Distal airway epithelial progenitors mediate TGF-β release to drive lung CD8+ TRM induction following mucosal BCG vaccination

A principal reason for the high global morbidity and mortality of tuberculosis (TB) is the lack of efficacy of the only licensed TB vaccine, Bacillus Calmette-Guérin (BCG), as intradermal BCG does not induce local pulmonary immune memory. Animal studies have shown that inhalation of BCG vaccination provides superior mucosal protection against TB due to generation of lung resident memory T cells (T_RM). Here, we demonstrated that following mucosal vaccination with the genetically modified more virulent BCG strain, BCG::RD1, distal airway epithelial progenitors were mobilized to assist with restoration of alveolar epithelium. By way of their integrin-mediated activation of latent TGF-β, lung CD8⁺ T_RM differentiation was induced. Mucosal vaccinations using nonvirulent strains of BCG in which airway epithelial progenitors were not mobilized, as well as genetic inhibition of integrin-mediated activation of TGF-β, resulted in significantly lower numbers of lung CD8⁺ T_RM with subsequent reduced protection against Mycobacterium tuberculosis (Mtb)-induced lung pathology in mice. The results link airway epithelial progenitor-mediated repair of injured lung tissue with a role in the induction of resident CD8⁺ T cell memory. These findings provide further explanation why mucosal vaccination with virulent BCG strains is more protective against TB and thus has implications for future TB vaccine development.