Francisella tularensis-infected macrophages release prostaglandin E 2 that blocks T cell proliferation and promotes a Th2-like response

Matthew D. Woolard, Justin E. Wilson, Lucinda L. Hensley, Leigh A. Jania, Thomas H. Kawula, James R. Drake, Jeffrey A. Frelinger

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

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 EL-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 syntliase 1 knockout mice (mPGES1-/-) that cannot produce PGE2. Supernatants from F. tularensis-infecied membrane PGE syntliase 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.

Original languageEnglish (US)
Pages (from-to)2065-2074
Number of pages10
JournalJournal of Immunology
Volume178
Issue number4
DOIs
StatePublished - Feb 15 2007
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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