(See for all publications Schliehe C in PubMed) Sarah Moser, MSc student Molecular Medicine (2016-2017).Max Lee, MSc student Molecular Medicine (2016-2017).Anne Rodenburg, MSc student Molecular Medicine (2017-2018).Tim Breugem, MSc student Infection and Immunity (2017-2018).Daryl Geers, MSc student Infection and Immunity (2019).Anneloes van Krimpen, MSc student Infection and Immunity (2019).Laure van Hofwegen, MSc student Infection and Immunity (2019-2020).Anoek Huijsmans, MSc student Infection and Immunity (2020).Izge Shanlitourk, MSc student Molecular Medicine (2020-2021).Marija Jokiç, MSc student Infection and Immunity (2020-2021).Manon Messchendorp, MSc student From Cells to Organisms, Leiden University (2021-2022).Ashish Ramlal, MSc student, Free University of Amsterdam (2022).Iris Manders, MSc student, University of Leiden (2022).Gunja Mishra, postdoctoral LEaDing Fellow (since 2019).Jane Voerman, research assistant (2016-2023).Sophie Shyfrin, MSc student Infection and Immunity (since 2023).Romy Kwakernaak, MSc student Infection and Immunity (since 2022). Mitchell Geleijnse, research assistant (since 2022).Currently we aim to translate your findings into clinically relevant models of cancer. These experiments were, to our knowledge, the first to investigate targeted pharmacologic protein degradation in the context of antigen presentation and our data point toward future applications by strategically combining therapies using bifunctional degraders with their stimulating effect on direct MHC class I presentation. Using different murine cell lines, we could show that the bifunctional molecule dTAG-7 induced rapid proteasome-dependent degradation of GFP-S8L-F12 and simultaneously increased its direct presentation on MHC class I molecules. We therefore generated the intrinsically stable model antigen GFP-S8L-F12 that was susceptible to acute pharmacologic degradation via the previously described degradation tag (dTAG) system. Two scenarios have been postulated: peptides can either be derived from homeostatic turnover of mature proteins and/or from short- lived defective ribosomal products (DRiPs), but currently, it is still unclear to what ratio and efficiency both pathways contribute to the overall MHC class I presentation. By studying this question, we contribute to the discussion about the origin of peptides feeding the MHC class I presentation pathway. For one of our research projects, we hypothesized that this process of acute pharmacologic protein degradation might increase the direct MHC class I presentation of degraded targets. They were designed to specifically target endogenous proteins for ubiquitin/proteasome-dependent degradation and to thereby interfere with pathological mechanisms of diseases, including cancer. Cross-presentation is the exclusive pathway by which CTLs can be primed against epitopes derived from cancer antigens or tissue-specific autoantigens.Įnhancing MHC class I presentation by bifunctional degraders (PROTACs):īifunctional degraders, also referred to as proteolysis-targeting chimeras (PROTACs), are a recently developed class of small molecules. This term describes the MHC class I presentation of exogenous antigens by professional APCs. The priming of CTL responses against tissue-specific antigens, which cannot be directly presented by APCs, requires an alternative pathway of MHC class I presentation, referred to as cross-presentation. This activation occurs via pattern recognition receptors (PRRs) that sense pathogen- and danger-associated molecules. To be fully functional, both CD8 + and CD4 + T-cells need a step of initial activation, called T-cell priming, which requires MHC presentation on activated APCs. MHC class II presentation is usually restricted to extracellular antigens and is recognized by CD4 + T-helper-cells that are important for immune regulation and activation of B-cell responses. Antigen presentation by MHC class II, in contrast, can only be performed by specialized cell types, so-called professional antigen presenting cells (APCs), including dendritic cells and macrophages. This pathway is referred to as the direct presentation pathway and it reflects a mechanism of immune surveillance to fight intracellular pathogens and cancer. The majority of cell types is able to present intracellular antigens on MHC class I, which is recognized by CD8 + cytotoxic T-cells (CTLs). Two classes of MHC presentation have been described. The antigen receptors of T-cells recognize short polypeptides presented on molecules of the major histocompatibility complex (MHC). The adaptive immune system efficiently clears pathogens by inducing antigen-specific responses.
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