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


RESULTS
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
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.
Schreiber
Heidi A
HA
Department of Pathology and Laboratory Medicine, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, United States of America.
Hulseberg
Paul D
PD
Lee
JangEun
J
Prechl
Jozsef
J
Barta
Peter
P
Szlavik
Nora
N
Harding
Jeffrey S
JS
Fabry
Zsuzsanna
Z
Sandor
Matyas
M
D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D060890:B7-H1 Antigen; D039521:CD11c Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D006099:Granuloma / Q000276:immunology* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009164:Mycobacterium Infections / Q000276:immunology; D009163:Mycobacterium bovis / Q000276:immunology; D061027:Programmed Cell Death 1 Ligand 2 Protein; D013601:T-Lymphocytes / Q000378:metabolism / Q000382:microbiology*
D000942:Antigens, Bacterial; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060890:B7-H1 Antigen; D039521:CD11c Antigen; C423236:CD274 protein, human; D019013:CD40 Antigens; D036341:Intercellular Signaling Peptides and Proteins; C556977:PDCD1LG2 protein, human; C556978:Pdcd1lg2 protein, mouse; D061027:Programmed Cell Death 1 Ligand 2 Protein; D007371:Interferon-gamma