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

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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Role of TNF-α in type 1 immune responses to treatment with dead mycobact...
Role of TNF-α in type 1 immune responses to treatment with dead mycobacteria (dBCG; a–c) or to infection by live replication-deficient auxotrophic mycobacteria (auBCG; d) or to treatment with mycobacterial cell wall components (CFA; e). B6-WT or TNF–/– mice were inoculated intratracheally (i.t.) with dBCG. Some TNF–/– mice were also injected intramuscularly with a dose of AdTNF at the time of dBCG administration. These mice were sacrificed at days 14 and 28. The level of IFN-γ was measured by ELISA in the BAL fluids, and the results are expressed as mean ± SEM from 4 mice per group (a) or culture supernatants of crude mycobacterial antigen (cBCG)-stimulated splenocytes isolated at days 14 (b) and 28 (c) after dBCG delivery. In some experiments, groups of 3 B6-WT and TNF–/– mice were infected i.v. with auBCG. Some TNF–/– were also injected with AdTNF or control vector Addl. The whole splenocytes were isolated and stimulated with mycobacterial antigens and culture supernatants measured for IFN-γ by ELISA (d). In other experiments, B6-WT and TNF–/– mice were injected intraperitoneally (i.p.) with complete Freund’s adjuvant (CFA). The whole splenocytes were isolated at day 27 and stimulated with M.tb cell wall antigens (M.tb CW) and culture supernatants measured for IFN-γ by ELISA (e).