Live Mycobacterium paragordonae induces heterologous immunity of natural killer cells by eliciting type I interferons from dendritic cells via STING-dependent sensing of cyclic-di-GMP.

Exploiting the heterologous effects of vaccines is a feasible strategy to combat different pathogens. These effects have been explained by enhanced immune responses of innate immune cells. Mycobacterium paragordonae is a rare nontuberculosis mycobacterium that has temperature-sensitive properties. Although natural killer (NK) cells exhibit heterologous immunity features, the cellular crosstalk between NK cells and dendritic cells (DCs) during live mycobacterial infection has remained elusive. We show that live but not dead M. paragordonae enhances heterologous immunity against unrelated pathogens in NK cells by IFN-β of DCs in both mouse models and primary human immune cells. C-di-GMP from live M. paragordonae acted as a viability-associated pathogen-associated molecular pattern (Vita-PAMP), leading to STING-dependent type I IFN production in DCs via the IRE1α/XBP1s pathway. Also, increased cytosolic 2'3'-cGAMP by cGAS can induce type I IFN response in DCs by live M. paragordonae infection. We found that DC-derived IFN-β plays a pivotal role in NK cell activation by live M. paragordonae infection, showing NK cell-mediated nonspecific protective effects against Candida albicans infection in a mouse model. Our findings indicate that the heterologous effect of live M. paragordonae vaccination is mediated by NK cells based on the crosstalk between DCs and NK cells.