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* Department of Microbiology and Immunology, University of North Carolina Chapel Hill, Chapel Hill, NC 27599;
Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208; and
Department of Genetics, University of North Carolina Chapel Hill, Chapel Hill, NC 27599
Francisella tularensis is a highly infectious bacterial pathogen, and is likely to have evolved strategies to evade and subvert the host immune response. In this study, we show that F. tularensis infection of macrophages alters T cell responses in vitro, by blocking T cell proliferation and promoting a Th2-like response. We demonstrate that a soluble mediator is responsible for this effect and identify it as PGE2. Supernatants from F. tularensis-infected macrophages inhibited IL-2 secretion from both MHC class I and MHC class II-restricted T cell hybridomas, as well as enhanced a Th2-like response by inducing increased production of IL-5. Furthermore, the soluble mediator blocked proliferation of naive MHC class I-restricted T cells when stimulated with cognate tetramer. Indomethacin treatment partially restored T cell proliferation and lowered IL-5 production to wild-type levels. Macrophages produced PGE2 when infected with F. tularensis, and treatment of infected macrophages with indomethacin, a cyclooxygenase-1/cyclooxygenase-2 inhibitor, blocked PGE2 production. To further demonstrate that PGE2 was responsible for skewing of T cell responses, we infected macrophages from membrane PGE synthase 1 knockout mice (mPGES1–/–) that cannot produce PGE2. Supernatants from F. tularensis-infected membrane PGE synthase 1–/– macrophages did not inhibit T cell proliferation. Furthermore, treatment of T cells with PGE2 recreated the effects seen with infected supernatant. From these data, we conclude that F. tularensis can alter host T cell responses by causing macrophages to produce PGE2. This study defines a previously unknown mechanism used by F. tularensis to modulate adaptive immunity.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by National Institutes of Health Grants PO1 AI056321, Subproject 1, National Institutes of Health/National Institute of Allergy and Infectious Diseases Southeast Regional Center of Excellence for Emerging Infections and Biodefense (Grant no. U54 AI 057157). M.D.W. was supported by a T32 Training Grant (AR07369-25). J.E.W. was supported by a T32 Training Grant (AI-49822) to the Center for Immunology and Microbial Disease.
2 M.D.W. and J.E.W. contributed equally to this manuscript.
3 Address correspondence and reprint requests to Dr. Jeffrey A. Frelinger, Department of Microbiology and Immunology, University of North Carolina, CB 7290, 804 Mary Ellen Jones Building, Chapel Hill, NC 27599. E-mail address: jfrelin{at}med.unc.edu
4 Abbreviations used in this paper: COX, cyclooxygenase; LVS, live vaccine strain; CPRG, chlorophenol red/3-galactoside; HEL, hen egg lysozyme; MOI, multiplicity of infection; iNOS, inducible NO synthase; mPGES, membrane PGE synthase.
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