Francisella tularensis elicits a soluble factor that induces ubiquitin‐dependent MHC class II endocytosis and degradation in macrophages

Abstract

The intracellular bacterium Francisella tularensis avoids degradation and replicates within macrophages (MØ), ultimately killing the host cell. Resolution of infection requires generation of IFN‐γ and development of adaptive immunity through presentation of F. tularensis antigens to CD4+ and CD8+ T cells. This laboratory has reported that F. tularensis induces MØ prostaglandin E2 (PGE2) production, leading to skewed T cell responses. PGE2 has been shown to downregulate MHC class II on MØs, suggesting that F. tularensis infection may alter T cell responses via inhibition of class II expression. To test this hypothesis, the effect of soluble factors produced by F. tularensis infected MØs on class II and CD86 expression by activated MØs was determined. Exposure of MØs to infection supernatants results in reduced surface class II and CD86. The factor eliciting class II downregulation is distinct from PGE2 and heat‐sensitive in nature. Moreover, biochemical analysis revealed a ubiquitin‐dependent mechanism of class II internalization and degradation within intracellular acidic compartments, and revealed that blocking this class II ubiquitination prevents surface clearance. These results suggest a mechanism for the modulation of MØ antigen presentation and T cell recognition during F. tularensis infection. Supported by NIH grant AI‐056320.