Mycobacterium tuberculosis Co-opts Monocytic Niches to Evade Immunity in Lymph Nodes

Mycobacterium tuberculosis (Mtb) not only establishes lung infection but also disseminates to lung-draining lymph nodes (LNs), where it can persist long-term. Paradoxically, these same LNs are critical for initiating protective T cell responses that help control infection. To understand how these divergent outcomes coexist within the same tissue, we examined the spatiotemporal dynamics of myeloid and CD4 T cell responses in the mediastinal LN (medLN) of mice after aerosol Mtb infection and BCG vaccination. During early infection (2-3 weeks), Mtb disseminated to the medLN via conventional dendritic cells (cDC) and monocytes, which localized to the T cell zone and typically harbored single bacilli. This phase was marked by robust Th1 priming, driven by IL-12-producing cDC1 and type I IFN-induced inflammatory cDC2s. By 3-4 weeks, however, cDC migration declined and medLNs became dominated by large monocyte-derived aggregates containing multiple bacilli. These aggregates exhibited alternative activation profiles and coincided with reduced T cell priming and Th1 differentiation. Strikingly, Mtb-specific T cells appeared unable to engage these infected aggregates, suggesting immunological ‘blindness’ to this niche. BCG vaccination curtailed Mtb burden and limited monocyte aggregate formation in the medLN without significantly altering myeloid trafficking or T cell priming, suggesting that vaccination impairs the formation of the monocytic niche rather than initial dissemination. Together, these findings reveal a narrow temporal window for effective T cell priming in LNs and identify a later-arising monocytic niche that supports Mtb persistence while evading immune recognition, highlighting how spatially organized host-pathogen interactions govern both protection and persistence during tuberculosis.