Mucosal Exposure to Non-Tuberculous Mycobacteria Elicits B Cell-Mediated Immunity Against Pulmonary Tuberculosis.

Bacille Calmette-Guerin (BCG) is the only licensed vaccine against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) disease. However, BCG has limited efficacy, necessitating the develop-ment of better vaccines. Non-tuberculous mycobacteria (NTMs) are opportunistic pathogens present ubiq-uitously in the environment. TB endemic countries experience higher exposure to NTMs, but previous studies have not elucidated the relationship between NTM exposure and BCG efficacy against TB. Therefore, we develop a mouse model (BCG + NTM) to simulate human BCG immunization regime and continuous NTM exposure. BCG + NTM mice exhibit superior and prolonged protection against pulmonary TB, with increased B cell influx and anti-Mtb antibodies in serum and airways, compared with BCG alone. Notably, spatial tran-scriptomics and immunohistochemistry reveal that BCG + NTM mice formed B cell aggregates with features of germinal center development, which correlate with reduced Mtb burden. Our studies suggest a direct rela-tionship between NTM exposure and TB protection, with B cells playing a crucial role.