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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Figure 1

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(a) Mortality of TNF–/– mice following infection by rBCG. Both B6-WT and...
(a) Mortality of TNF–/– mice following infection by rBCG. Both B6-WT and TNF–/– mice were infected intratracheally with rBCG, and the mortality of the mice was monitored thereafter. Results are from 15–20 mice per group, representative of more than two experiments. (b and c) Tissue level of mycobacterial infection. Infected B6-WT and TNF–/– mice were sacrificed at days 14, 27, and 37, and their lungs (b) and spleens (c) were homogenized and evaluated by using a colony enumeration assay. Results are expressed as mean ± SEM from 6–12 mice per group per time. The difference between B6-WT and TNF–/– at both days 27 and 37 is statistically very significant (P ≤ 0.01). (d) Hemoglobin oxygen saturation in the peripheral blood over the course of pulmonary mycobacterial infection. At various time points, the percentage of oxygen saturation of hemoglobin was measured on live mice by using a veterinary oximeter. Results are expressed as mean ± SEM from 5–10 mice per group per time point.