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TNF-α is a critical negative regulator of type 1 immune activation during intracellular bacterial infection
Anna Zganiacz, … , Mark Inman, Zhou Xing
Anna Zganiacz, … , Mark Inman, Zhou Xing
Published February 1, 2004
Citation Information: J Clin Invest. 2004;113(3):401-413. https://doi.org/10.1172/JCI18991.
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Article Infectious disease

TNF-α is a critical negative regulator of type 1 immune activation during intracellular bacterial infection

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Abstract

TNF-α has long been regarded as a proimmune cytokine involved in antimicrobial type 1 immunity. However, the precise role of TNF-α in antimicrobial type 1 immunity remains poorly understood. We found that TNF-α–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-γ and IL-12. Depletion of CD4 and CD8 T cells decreased IFN-γ levels, prevented granuloma and tissue necrosis, and prolonged the survival of TNF–/– hosts. Early reconstitution of TNF-α by gene transfer reduced the frequency of antigen-specific T cells and improved survival. TNF-α 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-α 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

Anna Zganiacz, Michael Santosuosso, Jun Wang, Tony Yang, Lihao Chen, Maria Anzulovic, Scott Alexander, Brigitte Gicquel, Yonghong Wan, Jonathan Bramson, Mark Inman, Zhou Xing

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