Sundquist, Malin2007-12-212007-12-212007-12-21978-91-628-7362-2http://hdl.handle.net/2077/8510The costimulatory molecules CD80 and CD86 are required for the ability of dendritic cells (DC) to induce both tolerance and immunity. This thesis investigates the control of CD80/CD86 upregulation in vivo on DC during Salmonella infection. After oral Salmonella infection, DC in Peyer´s patches (PP), mesenteric lymph nodes (MLN) and spleen upregulated costimulatory molecules almost simultaneously despite differential seeding of these organs with bacteria. Costimulatory molecules were also induced on TNF/iNOS-producing CD11cintCD11b+ DC that accumulated in infected organs. The CD11cintCD11b+ DC were efficient at bacterial uptake but, in contrast to conventional DC, failed to process and present Salmonella Ag on MHC-II. Using different gene-deficient mice, the pathways controlling CD80/86 upregulation on DC during Salmonella infection were dissected. Upregulation of CD80 was strictly dependent on the Toll-like receptor adaptor MyD88, whereas upregulation of CD86 was mediated by both MyD88-dependent and -independent factors. The pro-inflammatory cytokine TNF was identified as one MyD88-dependent factor required for optimal upregulation of CD80/86 in the MLN. In the absence of MyD88, upregulation of CD86 was mediated by type I interferons. However, the contribution of type I interferons to CD86 upregulation in wild type mice is only marginal, since mice lacking the type I interferon receptor (IFN-αβR) showed no major defects in CD80/86 upregulation. Despite the abrogated upregulation of CD80/86 on DC of TNFR1-/-, MyD88-/- or MyD88-/-IFN-αβR-/- mice, DC directly associated with bacteria upregulated costimulatory molecules independently of these factors. Pro-inflammatory signaling not only upregulated costimulatory molecules on DC during Salmonella infection, but also mediated DC death. Thus, MyD88-dependent production of TNF induced DC death in Salmonella-infected mice. CD8α+ DC were most susceptible to infection-induced cell death as assessed directly ex vivo by Annexin-V and 7AAD staining, whereas recruited CD11cintCD11b+ DC were completely resistant. Thus, the inflammatory environment imprints a distinct pattern of costimulatory molecules on DC, with MyD88-dependent factors controlling the upregulation of CD80. However, MyD88-dependent factors also induce DC death during Salmonella infection, which is likely to have a negative impact on anti-bacterial immunity.engDendritic cellsCostimulatory moleculesBacterial infectionPro-inflammatory cytokinesToll-like receptorsAg presentationCell deathtext