Optimizing DC cross-presentation, orchestrating the immune response

Abstract

Cord blood (CB) stem cell transplantation (SCT) is a last resort treatment for several malignancies, immune- and metabolic disorders. Although the safety of this procedure has improved over the past decades, room for improvement remains. Two of the major causes contributing to post-SCT mortality are disease relapse (in case of malignancies) and infectious complications. To be able to increase chances of survival, better therapies are warranted. As an approach for improved therapy, we focus on the development of a dendritic cell (DC)-vaccine aimed at inducing a rapid anti-viral or anti-tumor immune response. DCs are key players in initiation and control of adaptive immune responses due to their exquisite ability to present antigenic fragments in the form of peptide/major histocompatibility complexes (MHC) to T cells. This involves the classical antigen presentation routes where endogenously produces antigen is presented on class I MHC, while exogenously produces antigen is presented on class II MHC. A combination of these pathways also occurs. This process called cross-presentation, is most efficiently carried out by DCs and involves presentation of exogenously produces antigen on class I MHC molecules. Cross-presentation is an important mechanism by which DCs initiate CD8+ T cell immunity against viruses and cancer. In this thesis, we investigate the induction of antigen-specific CD8+ T cells by DC cross-presentation, and explore DC extrinsic and intrinsic factors to boost this process. In the first part of this thesis, we elaborate on the role of uptake receptors as well as CD4+ T-cells in human DC cross-priming and cross-presentation. Firstly, we show that uptake via the Fcγ-receptor leads to increased antigen cross-presentation. Secondly, we show that CD4+ T-cells are required for effective cross-priming of naïve CD8+ T-cells, and aid in effective cross-presentation to memory CD8+ T-cells. The second part of this thesis focuses on intracellular DC mechanisms that contribute to protein transport. We show the involvement of TLR- and ICAM-1 triggering in human DC tubulation, a process in which vesicles form elongated structures that speed-up protein transport. Then we show that tubulation accompanies DC antigen cross-presentation. In conclusion, this thesis describes the research of several DC extrinsic and intrinsic mechanisms that contribute to the understanding of antigen cross-presentation to CD8+ T cells. Findings described here should eventually lead to more effective DC vaccination regimens, in the end contributing to patient survival.