Dendritic cells in chronic mycobacterial granulomas restrict local anti-bacterial T cell response in a murine model

Heidi A. Schreiber, Paul D. Hulseberg, Jang Eun Lee, Jozsef Prechl, Peter Barta, Nora Szlavik, Jeffrey S. Harding, Zsuzsanna Fabry, Matyas Sandor

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29 Citations (Scopus)

Abstract

Background: Mycobacterium-induced granulomas are the interface between bacteria and host immune response. During acute infection dendritic cells (DCs) are critical for mycobacterial dissemination and activation of protective T cells. However, their role during chronic infection in the granuloma is poorly understood. Methodology/PrincipalFindings:We report that an inflammatory subset of murine DCs are present in granulomas induced by Mycobacteria bovis strain Bacillus Calmette-guerin (BCG), and both their location in granulomas and costimulatory molecule expression changes throughout infection. By flow cytometric analysis, we found that CD11c+ cells in chronic granulomas had lower expression of MHCII and co-stimulatory molecules CD40, CD80 and CD86, and higher expression of inhibitory molecules PD-L1 and PD-L2 compared to CD11c+ cells from acute granulomas. As a consequence of their phenotype, CD11c+ cells from chronic lesions were unable to support the reactivation of newly-recruited, antigen 85B-specific CD4+IFNγ+ T cells or induce an IFNγ response from naTve T cells in vivo and ex vivo. The mechanism of this inhibition involves the PD-1:PD-L signaling pathway, as ex vivo blockade of PD-L1 and PD-L2 restored the ability of isolated CD11c+ cells from chronic lesions to stimulate a protective IFNy T cell response. Conclusions/Significance: Our data suggest that DCs in chronic lesions may facilitate latent infection by down-regulating protective T cell responses, ultimately acting as a shield that promotes mycobacterium survival. This DC shield may explain why mycobacteria are adapted for long-term survival in granulomatous lesions.

Original languageEnglish
Article numbere11453
JournalPloS one
Volume5
Issue number7
DOIs
Publication statusPublished - aug. 13 2010

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Schreiber, H. A., Hulseberg, P. D., Lee, J. E., Prechl, J., Barta, P., Szlavik, N., Harding, J. S., Fabry, Z., & Sandor, M. (2010). Dendritic cells in chronic mycobacterial granulomas restrict local anti-bacterial T cell response in a murine model. PloS one, 5(7), [e11453]. https://doi.org/10.1371/journal.pone.0011453