Inflammatory dendritic cells migrate in and out of transplanted chronic mycobacterial granulomas in mice

Abstract

An estimated one-third of the world's population is infected with Mycobacterium tuberculosis, although most affected individuals maintain a latent infection. This control is attributed to the formation of granulomas, cell masses largely comprising infected macrophages with T cells aggregated around them. Inflammatory DCs, characterized as CD11c + CD11b + Ly6C + , are also found in granulomas and are an essential component of the acute immune response to mycobacteria. However, their function during chronic infection is less well understood. Here, we report that CD11c + cells dynamically traffic in and out of both acute and chronic granulomas induced by Mycobacterium bovis strain bacillus Calmette-Guérin (BCG) in mice. By transplanting Mycobacterium-induced granulomas containing fluorescently labeled CD11c + cells and bacteria into unlabeled mice, we were able to follow CD11c + cell trafficking and T cell activation. We found that half of the CD11c + cells in chronic granulomas were exchanged within 1 week. Compared with tissue-resident DC populations, CD11c + cells migrating out of granuloma-containing tissue had an unexpected systemic dissemination pattern. Despite low antigen availability, systemic CD4 + T cell priming still occurred during chronic infection. These data demonstrate that surveillance of granulomatous tissue by CD11c + cells is continuous and that these cells are distinct from tissue-resident DC populations and support T cell priming during both stages of Mycobacterium infection. This intense DC surveillance may also be a feature of Mycobacterium tuberculosis infection and other granuloma-associated diseases.

Immunity and Immunopathology in the Tuberculous Granuloma

“…Indeed, close temporal monitoring of the spread of infection from a primary granuloma focus tightly linked departing macrophages to the spread of infection. A similar phenomenon was recently documented in a transplantation model of TB in mice, where infected DCs were observed to exit the primary granuloma and spread the infection into distal tissues (Schreiber et al 2011). Although the mechanism of infected macrophage egress remains unclear, it does appear to be the main mode of establishing multiple infection foci early in infection.…”

Chronic Endotoxin Exposure Produces Airflow Obstruction and Lung Dendritic Cell Expansion

“…In contrast, in 8-week LPS mice, a significant increase was evident in the percentage of CD11b 1 DCs, a subset that was characterized as inflammatory DCs (8-week LPS mice, 47% 6 2.0%, versus 8-week PBS mice, 26% 6 3.1%) ( Figure 4E) (25). The term "inflammatory DC" refers to the subpopulation of cells characterized in the literature that are CD11b hi and have been observed in increased numbers in the setting of lung inflammation after a variety of stimuli (apart from chronic endotoxin, as described in this study), including ovalbumin (OVA) allergic lung inflammation, house dust mite allergic lung inflammation, lung infections, and cigarette smoke (23,(26)(27)(28)(29)(30)(31). These inflammatory DCs have been reported to involve distinct phenotypic and effector functions, and have been shown to arise from distinct blood precursors.…”

Pathology and immune reactivity: understanding multidimensionality in pulmonary tuberculosis

“…Ongoing inflammatory responses and continuous restructuring of the immune milieu imprint the dynamic features of granulomas. Myeloid cells, particularly dendritic cells, are recruited to, or egress from, granulomas [104,105], while mycobacteria-specific T cells show limited trafficking arrest in the lesions [104,106]. Superinfecting bacilli can also enter established granulomas [107] and this likely bears relevance for reinfection from exogenous sources as has been concluded from epidemiological data [108].…”