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Infection and Immunity, June 2002, p. 2959-2964, Vol. 70, No. 6
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.6.2959-2964.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Induction of Interleukin-12 and Gamma Interferon Requires Tumor Necrosis Factor Alpha for Protective T1-Cell-Mediated Immunity to Pulmonary Cryptococcus neoformans Infection

Amy C. Herring,1 John Lee,1 Roderick A. McDonald,1 Galen B. Toews,1 and Gary B. Huffnagle1,2*

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine,1 Department of Microbiology and Immunology, University of Michigan Medical Center, Ann Arbor, Michigan 481092

Received 9 August 2001/ Returned for modification 30 October 2001/ Accepted 7 March 2002

The development of T1-cell-mediated immunity is required to clear a pulmonary Cryptococcus neoformans infection. The objective of these studies was to determine the mechanism by which tumor necrosis factor alpha (TNF-{alpha}) augments the development of pulmonary T1 immunity to C. neoformans infection. TNF-{alpha} expression was detected in lavage sample cells at days 2, 3, and 7 following C. neoformans infection. The numbers of CFU in the lung were not different between control and anti-TNF-{alpha}-treated mice at any time point examined during the afferent phase of the response (days 0 to 7). However, neutralization of TNF-{alpha} prevented the initiation of pulmonary clearance during the efferent phase of the response (day 14). Administration of anti-TNF-{alpha} monoclonal antibody (day 0) diminished the lung levels of TNF-{alpha}, interleukin-12 (IL-12), and gamma interferon (IFN-{gamma}) induced by C. neoformans at day 7 postinfection. Neutralization of TNF-{alpha} (day 0) also altered the IFN-{gamma}/IL-4 ratio in the lung-associated lymph nodes at day 7 following C. neoformans infection. Anti-TNF-{alpha}-treated mice developed a pulmonary eosinophilia at day 14 postinfection. Consistent with the pulmonary eosinophilia, anti-TNF-{alpha}-treated mice exhibited elevated serum immunoglobulin E and inhibition of the anticryptococcal delayed-type hypersensitivity response, indicating a shift toward a T2 response. Neutralization of IL-12 also prevented lung leukocyte production of IFN-{gamma} in response to the infection. These findings demonstrate that afferent-phase TNF-{alpha} production is essential for the induction of IL-12 and IFN-{gamma} and neutralization of early TNF-{alpha} results in a T2 shift of the T1/T2 balance of antifungal immunity.

* Corresponding author. Mailing address: Pulmonary and Critical Care Medicine, 6301 MSRB III, The University of Michigan, Ann Arbor, MI 48109-0642. Phone: 734-936-9369. Fax: 734-764-4556. E-mail: ghuff{at}umich.edu.

Editor: R. N. Moore

Infection and Immunity, June 2002, p. 2959-2964, Vol. 70, No. 6
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.6.2959-2964.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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