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: Anna Zganiacz, Michael Santosuosso, Jun Wang, Tony Yang, Lihao Chen, Maria Anzulovic, Scott Alexander, Brigitte Gicquel, Yonghong Wan, Jonathan Bramson, Mark Inman, Zhou Xing
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 113 Issue 3 Pg. 401-13 (Feb 2004) ISSN: 0021-9738 [Print] United States
• PMID: 14755337 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Tumor Necrosis Factor-alpha

Topics

• Animals
• Apoptosis (immunology)
• Down-Regulation
• Immune System (immunology, metabolism)
• Mice
• Mycobacterium bovis (immunology)
• Signal Transduction (immunology)
• Tuberculosis (immunology, metabolism)
• Tumor Necrosis Factor-alpha (deficiency, genetics, immunology)