The mannose receptor influences antigen-presenting cells by direct interaction with CD45R0

The immune system has to manage the critical decision to induce either immunity or tolerance. Cells that take part in the regulatory processes of the immune system are amongst others antigen presenting cells (APCs), especially dendritic cells (DCs) and macrophages (M φΦs). Recently, it was shown that the mannose receptor (MR), known as an endocytic receptor expressed by specific APCs, is responsible for the induction of T cell tolerance. Under non-inflammatory conditions, the MR expressed by DCs can bind to CD45 on CD8+ T cells. The interaction of MR and CD45 induces the inhibition of CD45 phosphatase activity. Thereby, transcriptional T cell re-programming and up-regulation of CTLA-4 in T cells are initiated resulting in T cell tolerance. As CD45 is not only expressed by T cells but by all hematopoietic cells including APCs, the aim of this thesis was to investigate a putative influence of the MR on APCs by interaction with CD45. We could show that GM-CSF induced, bone marrow derived APCs (BM(GM-CSF) cells) express the lowest molecular isoform of CD45, CD45R0, that interacted with a recombinant MR construct comprising the CR, FN II, and CTLD1-2 domains of the MR (FcMR). This interaction impaired CD45 phosphatase activity in BM(GM-CSF) cells and altered intracellular signalling pathways. The capacity of APCs to stimulate antigen-specific T cells was altered by binding of FcMR to CD45. Antigen-specific T cells primed by FcMR pre-stimulated APCs showed reduced cytokine secretion of CD4+ T cells determined by IFN- γΓ levels and diminished cytotoxic activity of CD8+ T cells, although, proliferation of T cells remained unaffected. In addition, the application of supernatant containing soluble mannose receptor (sMR), that is shed by MR-positive cells, to stimulate BM(GM-CSF) cells also decreases CD45 phosphatase activity but in contrast supports an immunstimulatory phenotype of activated antigen-specific T cells. Recently, sMR was found to be highly elevated in several diseases. Here, we could show enhanced sMR serum levels after high-fat died or obesity in mice and human, respectively, pointing out a direct correlation of sMR expression and inflammatory metabolic processes

Current Concepts of Antigen Cross-Presentation

Dendritic cells have the ability to efficiently present internalized antigens on major histocompatibility complex (MHC) I molecules. This process is termed cross-presentation and is important role in the generation of an immune response against viruses and tumors, after vaccinations or in the induction of immune tolerance. The molecular mechanisms enabling cross-presentation have been topic of intense debate since many years. However, a clear view on these mechanisms remains difficult, partially due to important remaining questions, controversial results and discussions. Here, we give an overview of the current concepts of antigen cross-presentation and focus on a description of the major cross-presentation pathways, the role of retarded antigen degradation for efficient cross-presentation, the dislocation of antigens from endosomal compartment into the cytosol, the reverse transport of proteasome-derived peptides for loading on MHC I and the translocation of the cross-presentation machinery from the ER to endosomes. We try to highlight recent advances, discuss some of the controversial data and point out some of the major open questions in the field