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.
Granulomas are the interface between host and mycobacteria, and are crucial for the surivival of both species. While macrophages are the main cellular component of these lesions, different lymphocyte subpopulations within the lesions also play important roles. Lymphocytes are continuously recruited into these inflammatory lesions via local vessels to replace cells that are either dying or leaving; however, their rate of replacement is not known. Using a model of granuloma transplantation and fluorescently labeled cellular compartments we report that, depending on the subpopulation, 10–80%, of cells in the granuloma are replaced within one week after transplantation. CD4+ T cells specific for Mycobacterium antigen entered transplanted granulomas at a higher frequency than Foxp3+ CD4+ T cells by one week. Interestingly, a small number of T lymphocytes migrated out of the granuloma to secondary lymphoid organs. The mechanisms that define the differences in recruitment and efflux behind each subpopulation requires further studies. Ultimately, a better understanding of lymphoid traffic may provide new ways to modulate, regulate, and treat granulomatous diseases.
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