Inflammatory dendritic cells migrate in and out of transplanted chronic mycobacterial granulomas in mice
Heidi A. Schreiber, Jeffrey S. Harding, Oliver Hunt, Christopher J. Altamirano, Paul D. Hulseberg, Danielle Stewart, Zsuzsanna Fabry, Matyas Sandor
Heidi A. Schreiber, Jeffrey S. Harding, Oliver Hunt, Christopher J. Altamirano, Paul D. Hulseberg, Danielle Stewart, Zsuzsanna Fabry, Matyas Sandor
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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 7

Mycobacteria-specific Ag85B CD4+ T cell proliferation is dependent on MHCII expression on recipients’ cells.

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Mycobacteria-specific Ag85B CD4+ T cell proliferation is dependent on MH...
(A) 5 × 105 CFSE-labeled dsRED P25 CD4+ T cells were adoptively transferred into recipient C57BL/6 mice or MHCII-deficient mice 1 day prior to transplant of 3- and 10-week BCG-infected WT donors (3–5 mice per time point representative of 1–3 independent experiments), and 3- and 10-week BCG-infected Ccr7–/– donors (6 mice per time point). CFSE dilution histogram of Tg P25 CD4+ T cells in the tRLN 7 days after transplant. Numbers denote frequency of proliferating cells determined by set gate. Cells shown from same Tg gating strategy used in Figure 6C. (B) Mean percentage of P25 Tg CD4+ T cells 7 days after transplant in tRLN in cycle. Values obtained from gating strategy shown in A. Statistical significance from WT is as follows: ****P = 0.00001; ***P = 0.0001; **P = 0.001. Error bars represent mean ± SEM.