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

• Published in: PloS one Vol. 5; no. 7; p. e11453
• Main Authors: Schreiber, Heidi A, Hulseberg, Paul D, Lee, JangEun, Prechl, Jozsef, Barta, Peter, Szlavik, Nora, Harding, Jeffrey S, Fabry, Zsuzsanna, Sandor, Matyas
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06.07.2010; Public Library of Science (PLoS)
• Subjects: Animal models; Animals; Antibacterial agents; Antigen 85B; Antigens; Antigens, Bacterial - immunology; Antigens, CD - metabolism; Antiinfectives and antibacterials; B cells; B7-1 Antigen - metabolism; B7-2 Antigen - metabolism; B7-H1 Antigen; Bacillus Calmette-Guerin vaccine; Bacteria; BCG; CD11c antigen; CD11c Antigen - metabolism; CD4 antigen; CD4-Positive T-Lymphocytes - metabolism; CD40 antigen; CD40 Antigens - metabolism; CD80 antigen; CD86 antigen; Cell activation; Cell survival; Cells, Cultured; Chronic infection; Cost analysis; Costimulator; Cytokines; Data processing; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Flow Cytometry; Gene expression; Granuloma; Granuloma - immunology; Granuloma - metabolism; Health aspects; Immune response; Immune system; Immunoglobulins; Immunology; Immunology/Cellular Microbiology and Pathogenesis; Immunology/Immune Response; Immunology/Immunity to Infections; Infection; Infections; Infectious Diseases/Bacterial Infections; Inflammation; Intercellular Signaling Peptides and Proteins - metabolism; Interferon-gamma - metabolism; Laboratories; Latent infection; Lesions; Lymphocytes; Lymphocytes T; Medicine; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence; Mycobacterium; Mycobacterium avium; Mycobacterium bovis; Mycobacterium bovis - immunology; Mycobacterium Infections - immunology; Mycobacterium tuberculosis; Pathology; PD-1 protein; PD-L1 protein; Programmed Cell Death 1 Ligand 2 Protein; Public health; Rodents; Signal transduction; Signaling; Survival; T cells; T-Lymphocytes - metabolism; T-Lymphocytes - microbiology; Training; Tuberculosis; γ-Interferon; San Francisco California; California; Hungary; United States > US; Wisconsin
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0011453

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. 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. 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.