TNF-alpha is a critical negative regulator of type 1 immune activation during intracellular bacterial infection.
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.
Zganiacz
Anna
A
Infectious Diseases Division, Centre for Gene Therapeutics, and Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Santosuosso
Michael
M
Wang
Jun
J
Yang
Tony
T
Chen
Lihao
L
Anzulovic
Maria
M
Alexander
Scott
S
Gicquel
Brigitte
B
Wan
Yonghong
Y
Bramson
Jonathan
J
Inman
Mark
M
Xing
Zhou
Z
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*
D014409:Tumor Necrosis Factor-alpha