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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

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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 1

CD11c+ cells in acute and chronic granulomas.

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CD11c+ cells in acute and chronic granulomas.
   
C57BL/6 mice were syst...
C57BL/6 mice were systemically infected i.p. with BCG. (A) H&E staining of formalin-fixed liver tissue showing 3- and 10-week granulomas. Original magnification, ×400. (B) Top panels, CD11c and CD11b populations in liver granuloma cell suspensions. Plot obtained by gating on the population displaying high side scatter (SSC) and forward scatter (FSC), excluding lymphocytes. Numbers within gate denote frequency of CD11c+ cells within high SSC and high FSC population. Bottom panels, Ly6C expression on gated CD11c+ population from above plots. Gate set based on known Ly6C-negative populations and numbers denote distribution of Ly6C-positive and -negative expression on CD11c+ population. (C) Original magnification, ×100. Fluorescent microscopy image taken of liver from CD11c-EYFP mouse infected for 10 weeks with dsRED BCG. Granulomas outlined with white dashed lines. CD11c-EYFP cells are shown in green, and DAPI nuclear stain in blue. (D) Digital magnification of red box in C. Original magnification, ×1000. Red arrows point to dsRED BCG rods. (E) CD11c-EFYP cell from D with anti-CD4 staining (red). Red arrow points to CD4+ cell, and yellow arrow points to merged CD4+YFP+ staining. Original magnification, ×1000. (F) Representation of observations in D and E. Representative plots and images from at least 3 or more independent experiments.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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