title: TNF-alpha is a critical negative regulator of type 1 immune activation during intracellular bacterial infection.
abstract: TNF-alpha has long been regarded as a proimmune cytokine involved in antimicrobial type 1 immunity. However, the precise role of TNF-alpha in antimicrobial type 1 immunity remains poorly understood. We found that TNF-alpha-deficient (TNF(-/-)) mice quickly succumbed to respiratory failure following lung infection with replication-competent mycobacteria, because of apoptosis and necrosis of granuloma and lung structure. Tissue destruction was a result of an uncontrolled type 1 immune syndrome characterized by expansion of activated CD4 and CD8 T cells, increased frequency of antigen-specific T cells, and overproduction of IFN-gamma and IL-12. Depletion of CD4 and CD8 T cells decreased IFN-gamma levels, prevented granuloma and tissue necrosis, and prolonged the survival of TNF(-/-) hosts. Early reconstitution of TNF-alpha by gene transfer reduced the frequency of antigen-specific T cells and improved survival. TNF-alpha controlled type 1 immune activation at least in part by suppressing T cell proliferation, and this suppression involved both TNF receptor p55 and TNF receptor p75. Heightened type 1 immune activation also occurred in TNF(-/-) mice treated with dead mycobacteria, live replication-deficient mycobacteria, or mycobacterial cell wall components. Our study thus identifies TNF-alpha as a type 1 immunoregulatory cytokine whose primary role, different from those of other type 1 cytokines, is to keep an otherwise detrimental type 1 immune response in check.
authors.affiliation: Infectious Diseases Division, Centre for Gene Therapeutics, and Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Zganiacz
authors.forename: Michael
authors.initials: M
authors.lastname: Santosuosso
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Tony
authors.initials: T
authors.lastname: Yang
authors.forename: Lihao
authors.initials: L
authors.lastname: Chen
authors.forename: Maria
authors.initials: M
authors.lastname: Anzulovic
authors.forename: Scott
authors.initials: S
authors.lastname: Alexander
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gicquel
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Wan
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bramson
authors.forename: Mark
authors.initials: M
authors.lastname: Inman
authors.forename: Zhou
authors.initials: Z
authors.lastname: Xing
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015536:Down-Regulation; D007107:Immune System / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D009163:Mycobacterium bovis / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
chemical_list: D014409:Tumor Necrosis Factor-alpha