title: Pulmonary mycobacterial granuloma increased IL-10 production contributes to establishing a symbiotic host-microbe microenvironment.
abstract: The granuloma, a hallmark of host defense against pulmonary mycobacterial infection, has long been believed to be an active type 1 immune environment. However, the mechanisms regarding why granuloma fails to eliminate mycobacteria even in immune-competent hosts, have remained largely unclear. By using a model of pulmonary Mycobacterium bovis Bacillus Calmette-Guerin (BCG) infection, we have addressed this issue by comparing the immune responses within the airway luminal and granuloma compartments. We found that despite having a similar immune cellular profile to that in the airway lumen, the granuloma displayed severely suppressed type 1 immune cytokine but enhanced chemokine responses. Both antigen-presenting cells (APCs) and T cells in granuloma produced fewer type 1 immune molecules including tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and nitric oxide. As a result, the granuloma APCs developed a reduced capacity to phagocytose mycobacteria and to induce T-cell proliferation. To examine the molecular mechanisms, we compared the levels of immune suppressive cytokine IL-10 in the airway lumen and granuloma and found that both granuloma APCs and T cells produced much more IL-10. Thus, IL-10 deficiency restored type 1 immune activation within the granuloma while having a minimal effect within the airway lumen. Hence, our study provides the first experimental evidence that, contrary to the conventional belief, the BCG-induced lung granuloma represents a symbiotic host-microbe microenvironment characterized by suppressed type 1 immune activation.
authors.affiliation: Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics, and M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Shaler
authors.forename: Kapilan
authors.initials: K
authors.lastname: Kugathasan
authors.forename: Sarah
authors.initials: S
authors.lastname: McCormick
authors.forename: Daniela
authors.initials: D
authors.lastname: Damjanovic
authors.forename: Carly
authors.initials: C
authors.lastname: Horvath
authors.forename: Cherrie-Lee
authors.initials: CL
authors.lastname: Small
authors.forename: Mangalakumari
authors.initials: M
authors.lastname: Jeyanathan
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.forename: Ping-Chang
authors.initials: PC
authors.lastname: Yang
authors.forename: Zhou
authors.initials: Z
authors.lastname: Xing
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism; D001500:BCG Vaccine / Q000378:metabolism; D039481:CD11b Antigen / Q000096:biosynthesis; D039521:CD11c Antigen / Q000096:biosynthesis; D049109:Cell Proliferation; D005260:Female; D006099:Granuloma / Q000382:microbiology*; D007107:Immune System; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009163:Mycobacterium bovis / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D013559:Symbiosis; D013601:T-Lymphocytes / Q000166:cytology / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001500:BCG Vaccine; D039481:CD11b Antigen; D039521:CD11c Antigen; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D009569:Nitric Oxide; D007371:Interferon-gamma