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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(a) IL-12 levels in BAL fluids. (b) IFN-γ levels in BAL fluids. These cy...
(a) IL-12 levels in BAL fluids. (b) IFN-γ levels in BAL fluids. These cytokines were measured by using ELISA kits. Results are expressed as mean ± SEM from 5–9 mice per group per time point. The difference between B6-WT and TNF–/– at day 37 is statistically very significant (P ≤ 0.01) (a and b). (c and d) Immune phenotypes of T cells in the lung (c) and thoracic lymph nodes (LN) (d). Pooled cells from several mice per group were subject to FACS staining and analysis by the use of monoclonal antibodies for CD3, CD4, CD8, and CD69. T cell subsets were identified as those coexpressing CD3/CD4, CD3/CD8, CD3/CD4/CD69 and CD3/CD8/CD69. The numbers in the parentheses represent the fold increase in each subset of lymphocytes over B6-WT controls. (e) Antigen-specific IFN-γ responses in whole lymphocytes of lymphoid organs. Total lymphocytes were isolated from pooled spleens of several mice per group at various time points after pulmonary rBCG mycobacterial infection and cultured with or without mycobacterial antigens (M.tb CF). Supernatants were measured for IFN-γ by ELISA. Results are expressed as mean ± SEM of triplicate wells, representative of 2–3 independent experiments. Differences between B6-WT and TNF–/– at days 14, 27 and 37 are all statistically very significant (P ≤ 0.01). (f) Relative contribution of CD4 and CD8 T cells to antigen-specific IFN-γ release. At day 27, purified splenocytes were cultured with or without M.tb CF and control normal rat IgG (C.Ab), and anti-CD4 or anti-CD8 monoclonal antibody or both, and supernatants were measured for IFN-γ release by ELISA. Results are expressed as mean ± SEM from triplicate wells per time point or condition. The difference between C.Ab and antibody-treated cultures is statistically very significant (P ≤ 0.01). Ag, antigen.