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 5

CD11c-EYFP+ migration into transplanted granulomas.

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CD11c-EYFP+ migration into transplanted granulomas. Noninfected or 3...
Noninfected or 3- or 10-week-infected liver pieces from colorless donors were transplanted into CD11c-EYFP recipients. (A) 3 and 7 days post transplant (dpt), donor liver tissue was excised and prepared for flow cytometry. CD11c-EYFP histograms generated from CD11c+ surface stain gate. Numbers denote frequency of CD11c-EYFP positive and negative cells among total CD11c+ population. (B) Fluorescent microscopy images of transplanted kidney 3 and 7 days after transplant. In first and third columns, white dashed lines indicate borders of transplanted piece and kidney. In second and fourth columns, red indicates donor anti-CD11c surface stain (D), and green or yellow/orange indicate recipient CD11c+ cell (R). Original magnification, ×400 (first and third columns); ×1000 (second and fourth columns). D, donor; R, recipient. (C) Mean distribution of all donor (white bars) and recipient (gray bars) CD11c+ cells per granuloma 3 and 7 days after transplant. CD11c+ cellular distribution was determined from 10 granulomas per time point. (D) Histograms showing surface expression of MHCII and activating costimulatory molecules CD40 and CD86. Red dashed line represents background expression. (E) Mean MFI of MHCII and costimulatory molecule expression. Data shown representative of 2 independent experiments with 4 kidneys per group. **P < 0.05; ***P < 0.001. Error bars represent mean ± SEM.