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Modulation of macrophage antigen presentation by Francisella tularensis.

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Overview

The intracellular bacterium Francisella tularensis avoids degradation and replicates within macrophages, ultimately killing the host cell. Resolution of infection requires generation of the Th1 cytokines IFN-gamma and TNF-alpha and development of adaptive immunity through presentation of F. tularensis antigens to CD4+ and CD8 + T cells. Using a T cell hybridoma-based model system, we have reported that macrophages infected with F. tularensis produce prostaglandin E2 (PGE2) that induces a shift in the T cell cytokine profile from IL-2 to IL-5 in response to antigen presentation. Inhibition of prostaglandin synthesis with a cyclooxygenase inhibitor partially restores the cytokine profile and addition of exogenous PGE2 to the antigen presentation assay or to antibody-stimulated T cells results in a similar cytokine switch observed with F. tularensis infected macrophages. Further results indicate that F. tularensis surface characteristics are at least partially responsible for PGE2-mediated skewing T cell cytokine responses as disruption of bacterial surface carbohydrate groups and deletion of F. tularensis capsule genes prevents the induction of IL-5 production by T cells.;In addition to skewing T cell responses towards a Th2-like profile, PGE 2 has also been shown to downregulate MHC class II on macrophages, suggesting that F. tularensis infection may alter T cell responses via inhibition of class II expression. To test this hypothesis, IFN-gamma-activated reporter macrophages were exposed to supernatants from F. tularensis infected macrophages and MHC class II levels were measured. Exposure of macrophages to infection supernatants resulted in essentially complete clearance of surface MHC class II and CD86. Biochemical analysis revealed that infection supernatants elicit ubiquitin dependent MHC class II downregulation and degradation within intracellular acidic compartments. By comparison, PGE 2 alone leads to a minor loss of class II expression, demonstrating that macrophage class II downregulation was mediated by a factor distinct from PGE2. Moreover, fractionation of F. tularensis infection supernatants demonstrates that unlike PGE2, this factor is >10 kD in size. However, production of this >10 kD, non-PGE2 factor was dependent on macrophage cyclooxygenase activity and could be induced by PGE2, suggesting PGE2 is indirectly responsible for eliciting reduced macrophage class II expression. Furthermore, production of this factor was independent of the activation state of the macrophage and bacterial viability.;These results establish that F. tularensis has the ability to induce the production of PGE2 from macrophages, which can skew T cell cytokine responses away from inflammatory Th-1 like responses towards an inappropriate Th-2-like response. Furthermore, F. tularensis elicited PGE2 also induces the production one or more PGE 2-dependent macrophage factor(s) that elicits MHC class II down-regulation in IFN-gamma activated macrophages through ubiquitin-mediated delivery of class II to lysosomal compartments, demonstrating multiple mechanisms for the modulation of T cell responses and macrophage antigen presentation during F. tularensis infection.
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Product Details

  • ISBN-13: 9781109150575
  • Publisher: ProQuest LLC
  • Sold by: Barnes & Noble
  • Format: eTextbook
  • Pages: 164
  • File size: 3 MB

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