Monocytic niches escape T cell surveillance and promote Mycobacterium tuberculosis persistence in lymph nodes.

Lung-draining mediastinal lymph nodes (medLNs) are critical for Mycobacterium tuberculosis (Mtb) pathogenesis, serving both as sites of T cell priming and, paradoxically, reservoirs for long-term bacterial persistence. To understand this dichotomy, we examined myeloid and CD4+ T cell dynamics in medLNs after aerosol Mtb infection. Early bacterial dissemination occurred via monocytes and interleukin (IL)-12-producing conventional dendritic cells (cDCs), which initiated T helper 1 (Th1) cell priming within the T cell zone. Over time, cDC migration and T cell activation declined, and medLNs became dominated by heavily infected monocyte-derived aggregates that persisted into late infection. Despite inducing proinflammatory and bactericidal pathways, these aggregates escaped recognition by Mtb-specific T cells and failed to clear Mtb, thereby forming an immunologically "blind" niche. Bacille Calmette-Guérin (BCG) vaccination reduced Mtb burden and niche establishment without altering myeloid trafficking or T cell priming. Thus, Mtb persists in medLNs within monocytic niches, eliciting classical antimicrobial programs that are insufficient for sterilizing control.