Infection models based on human primary cells can uniquely capture the differential trajectories of immune responses from different individuals following challenge with Mycobacterium tuberculosis (Mtb) ex vivo. In that context, my lab’ implemented a 3-dimensional (3D) granuloma-like model (3DGran) based on human PBMCs embedded in a matrix of collagen and fibronectin mimicking the lung tissue interstitium, in which granuloma-like structures form spontaneously upon Mtb infection. The model can capture the virulence propensities of different Mtb clinical isolates, the protective role of GM-CSF and the recreation of hypoxic conditions driving Mtb dormancy, a phenotypic state associated with accumulation of lipid droplets. While Mtb exploits human immune cells to replicate in that system, different donors are not equally permissive. In that context, we recently applied mass cytometry (CyTOF) to 3DGran from clinical specimens of TB patients to unravel a new immune escape mechanism of Mtb to cytotoxic lymphocyte activity.