Inflammatory dendritic cells migrate in and out of transplanted chronic mycobacterial granulomas in mice
Heidi A. Schreiber, … , Zsuzsanna Fabry, Matyas Sandor
Heidi A. Schreiber, … , Zsuzsanna Fabry, Matyas Sandor
Published September 12, 2011
Citation Information: J Clin Invest. 2011;121(10):3902-3913. https://doi.org/10.1172/JCI45113.
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Research Article Infectious disease

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.

Authors

Heidi A. Schreiber, Jeffrey S. Harding, Oliver Hunt, Christopher J. Altamirano, Paul D. Hulseberg, Danielle Stewart, Zsuzsanna Fabry, Matyas Sandor

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Figure 6

Proliferation of Mycobacteria-specific Ag85B CD4+ T cells after transplant of acutely and chronically infected liver tissue.

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Proliferation of Mycobacteria-specific Ag85B CD4+ T cells after transpla...
(A) Fluorescent microscopy of transplant tRLN 7 days after transplant. CD11c-EYFP cells (green), and CD4+ T cells (red). Yellow arrows point to merged green and red staining. Original magnification, ×1000. (B) Experimental schematic. Briefly, CD11c-EYFP mice were systemically infected with dsRED BCG for 3 weeks, 10 weeks, or 7 months. 1 day prior to transplant, 5 × 105 CFSE-labeled dsRED Ag85B CD4+ T cells were adoptively transferred. 7 days after transplant, the tRLNs were removed and analyzed by flow cytometry. (C) Top row: adoptively transferred Tg T cells were identified by CD4+dsRED+ gating, plots shown were obtained from lymphocyte gate on SSC versus FSC plot. Bottom 2 rows: CFSE dilution histogram from Tg gate from upper row. (D) Graph shows average percentage of dsRED Ag85B CD4+ T cells in cycle. Graph representative of 2–5 independent experiments per time point with an average of 2–6 mice per group. Error bars represent mean ± SEM, and statistical significance between groups is shown in graph.