Granulysin Antimicrobial Activity Promotes Dormancy in Mycobacterium tuberculosis.

Human tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) remains a global public health threat. Granulomas constitute a hallmark of TB pathogenesis that can clear, contain, or exacerbate an infection. Containment is exploited by Mtb as a hideout to persist in a dormant, antibiotic-tolerant state, only to resuscitate upon immunosuppression. The immune determinants of a granulomatous response driving Mtb persistence remain elusive. We here generated ex vivo granuloma-like structures from peripheral blood mononuclear cell specimens of TB patients and applied high-dimensional mass cytometry to elucidate immune factors prompting Mtb dormancy. Compared with healthy controls, patient-derived specimens rapidly forced Mtb to become dormant-like ex vivo. This observation correlated with an enrichment in activated, innate (-like) cytotoxic lymphocytes and required the presence of CD56 lymphocytes or, more specifically, the content of their granules. Finally, we demonstrated that direct exposure to granulysin induces Mtb dormancy, thereby unravelling an immune escape mechanism to cytotoxic lymphocyte activity.