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Infection and Immunity, April 2002, p. 1936-1948, Vol. 70, No. 4
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.4.1936-1948.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

In Vivo Clearance of an Intracellular Bacterium, Francisella tularensis LVS, Is Dependent on the p40 Subunit of Interleukin-12 (IL-12) but Not on IL-12 p70

Karen L. Elkins,* Allison Cooper, Susan M. Colombini, Siobhán C. Cowley, and Tara L. Kieffer

Laboratory of Mycobacteria, Division of Bacterial, Parasitic, and Allergenic Products, CBER/FDA, Rockville, Maryland 20852

Received 26 September 2001/ Returned for modification 20 December 2001/ Accepted 10 January 2002

To determine the role of interleukin-12 (IL-12) in primary and secondary immunity to a model intracellular bacterium, we have comprehensively evaluated infection with Francisella tularensis LVS in three murine models of IL-12 deficiency. Mice lacking the p40 protein of IL-12 (p40 knockout [KO] mice) and mice treated in vivo with neutralizing anti-IL-12 antibodies survived large doses of primary and secondary LVS infection but never cleared bacteria and exhibited a chronic infection. In dramatic contrast, mice lacking the p35 protein (p35 KO mice) of heterodimeric IL-12 readily survived large doses of primary sublethal LVS infection as well as maximal secondary lethal challenge, with only a slight delay in clearance of bacteria. LVS-immune wild-type (WT) lymphocytes produced large amounts of gamma interferon (IFN-{gamma}), but p35 KO and p40 KO lymphocytes produced much less; nonetheless, similar amounts of NO were found in all cultures containing immune lymphocytes, and all immune lymphocytes were equally capable of controlling intracellular growth of LVS in vitro. Purified CD4+ and CD8+ T cells from both WT and p40 KO mice controlled intracellular growth, even though T cells from WT mice produced much more IFN-{gamma} than those from p40 KO mice, and p40 KO T cells did not adopt a Th2 phenotype. Thus, while IL-12 p70 stimulation of IFN-{gamma} production may be important for bacteriostasis, IL-12 p70 is not necessary for appropriate development of LVS-immune T cells that are capable of controlling intracellular bacterial growth and for clearance of primary or secondary LVS infection. Instead, an additional mechanism dependent on the IL-12 p40 protein, either alone or in another complex such as the newly discovered heterodimer IL-23, appears to be responsible for actual clearance of this intracellular bacterium.

* Corresponding author. Mailing address: LOM/DBPAP/CBER/FDA, 1401 Rockville Pike, HFM 431, Rockville, MD 20852. Phone: (301) 496-0544. Fax: (301) 402-2776. E-mail: elkins{at}cber.fda.gov.

Editor: R. N. Moore

Infection and Immunity, April 2002, p. 1936-1948, Vol. 70, No. 4
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.4.1936-1948.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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