Abstract
Francisella tularensis is a bacterial pathogen that uses host-derived PGE2 to subvert the host's adaptive immune responses in multiple ways. Francisella-induced PGE2 acts directly on CD4 T cells to blunt production of IFN-γ. Francisella-induced PGE2 can also elicit production of a >10 kDa soluble host factor termed FTMØSN (F. tularensis macrophage supernatant), which acts on IFN-γ pre-activated MØ to down-regulate MHC class II expression via a ubiquitin-dependent mechanism, blocking antigen presentation to CD4 T cells. Here, we report that FTMØSN-induced down-regulation of MØ class II is the result of the induction of MARCH1, and that MØ expressing MARCH1 “resistant” class II molecules are resistant to FTMØSN-induced class II down-regulation. Since PGE2 can induce IL-10 production and IL-10 is the only reported cytokine able to induce MARCH1 expression in monocytes and dendritic cells, these findings suggested that IL-10 is the active factor in FTMØSN. However, use of IL-10 knockout MØ established that IL-10 is not the active factor in FTMØSN, but rather that Francisella-elicited PGE2 drives production of a >10 kDa host factor distinct from IL-10. This factor then drives MØ IL-10 production to induce MARCH1 expression and the resultant class II down-regulation. Since many human pathogens such as Salmonella typhi, Mycobacterium tuberculosis and Legionella pneumophila also induce production of host PGE2, these results suggest that a yet-to-be-identified PGE2-inducible host factor capable of inducing IL-10 is central to the immune evasion mechanisms of multiple important human pathogens.
Highlights
F. tularensis is a bacterial pathogen that infects macrophages and uses host-derived PGE2 to enhance bacterial growth and subvert the adaptive immune response [1]
Previous studies have established that Francisella tularensisinfected MØ produce PGE2, which can both alter CD4 T cell cytokine production and drive the production of a soluble factor (i.e., FTMØSN) that elicits the ubiquitin-dependent downregulation of MØ MHC class II expression [7]
Since other clinically relevant human pathogens such as Salmonella typhi [2,3], Mycobacterium tuberculosis [4] and Legionella pneumophila [5] elicit host PGE2, it was of interest to determine the mechanism of FTMØSN-induced MØ class II down-regulation
Summary
F. tularensis is a bacterial pathogen that infects macrophages and uses host-derived PGE2 to enhance bacterial growth and subvert the adaptive immune response [1]. Francisella-induced PGE2, which is elicited by either the live vaccine strain (LVS) or human virulent SchuS4 strain of Francisella, acts in an autocrine/paracrine fashion to drive production of a soluble MØ factor that elicits the ubiquitindependent down-regulation of MHC class II and CD86 molecules expressed by IFN-c activated MØ [7] (Figure 1). The factor within this F. tularensis MØ supernatant (termed FTMØSN, pronounced foot-mo-sin) drives MØ class II down-regulation by eliciting ubiquitination of the class II cytoplasmic tail, which results in class II trafficking to degradative intracellular compartments [7,8]. The resulting class II negative MØ are greatly impaired in their ability to present antigens to CD4 T cells
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