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

PLoS One. 2010 Jul 6;5(7):e11453. doi: 10.1371/journal.pone.0011453.


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/principal findings: 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(+)IFNgamma(+) T cells or induce an IFNgamma response from naïve 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 IFNgamma 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, Bacterial / immunology
  • Antigens, CD / metabolism
  • B7-1 Antigen / metabolism
  • B7-2 Antigen / metabolism
  • B7-H1 Antigen
  • CD11c Antigen / metabolism
  • CD4-Positive T-Lymphocytes / metabolism
  • CD40 Antigens / metabolism
  • Cells, Cultured
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Flow Cytometry
  • Granuloma / immunology*
  • Granuloma / metabolism
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Interferon-gamma / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence
  • Mycobacterium Infections / immunology
  • Mycobacterium bovis / immunology
  • Programmed Cell Death 1 Ligand 2 Protein
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / microbiology*


  • Antigens, Bacterial
  • Antigens, CD
  • B7-1 Antigen
  • B7-2 Antigen
  • B7-H1 Antigen
  • CD11c Antigen
  • CD274 protein, human
  • CD40 Antigens
  • Intercellular Signaling Peptides and Proteins
  • PDCD1LG2 protein, human
  • Pdcd1lg2 protein, mouse
  • Programmed Cell Death 1 Ligand 2 Protein
  • Interferon-gamma