The Journal of Experimental Medicine
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Published online 28 July 2003 doi:10.1084/jem.20030687
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© Rockefeller University Press, 0022-1007/2003/8/379 $5.00
The Journal of Experimental Medicine, Volume 198, Number 3, 379-389

Multiple T Cell Subsets Control Francisella tularensis LVS Intracellular Growth Without Stimulation Through Macrophage Interferon {gamma} Receptors

Siobhán C. Cowley and Karen L. Elkins

Laboratory of Mycobacterial Diseases and Cellular Immunology, Division of Bacterial, Parasitic, and Allergenic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, MD 20852

Address correspondence to Dr. Siobhán Cowley, LMDCI/DBPAP/CBER/FDA, 1401 Rockville Pike, HFM 431, Rockville, MD 20852. Phone: 301-496-850; Fax: 301-435-5675; email: cowley{at}cber.fda.gov; or Dr. Karen L. Elkins. Phone: 301-496-0544; Fax: 301-435-5675; email: elkins{at}cber.fda.gov

A variety of data suggest that in vivo production of interferon (IFN)-{gamma} is necessary, but not sufficient, for expression of secondary protective immunity against intracellular pathogens. To discover specific IFN-{gamma}–independent T cell mediated mechanisms, we took advantage of an in vitro culture system that models in vivo immune responses to the intracellular bacterium Francisella tularensis live vaccine strain (LVS). LVS-immune lymphocytes specifically controlled 99% of the growth of LVS in wild-type murine bone marrow–derived macrophages. Surprisingly, LVS-immune lymphocytes also inhibited LVS intracellular growth by as much as 95% in macrophages derived from IFN-{gamma} receptor knockout (IFN{gamma}R KO) mice. CD8+ T cells, and to a lesser degree CD4+ T cells, controlled LVS intracellular growth in both wild-type and IFN{gamma}R KO macrophages. Further, a unique population of Thy1+{alpha}ß+CD4-CD8- cells that was previously suggested to operate during secondary immunity to LVS in vivo strongly controlled LVS intracellular growth in vitro. A large proportion of the inhibition of LVS intracellular growth in IFN{gamma}R KO macrophages by all three T cell subsets could be attributed to tumor necrosis factor (TNF) {alpha}. Thus, T cell mechanisms exist that control LVS intracellular growth without acting through the IFN-{gamma} receptor; such control is due in large part to TNF-{alpha}, and is partially mediated by a unique double negative T cell subpopulation.

Key Words: protective immunity • Francisella tularensis LVS • interferon {gamma} • TNF-{alpha} • T cells


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