Professor W. (Willem) Stoorvogel, PhD
Tuesday 9 October 2012
Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, UU
Prof.dr. Willem Stoorvogel,
Adaptive immune responses are initiated and specified by dendritic cells (DCs). DCs reside throughout peripheral tissues where they capture extracellular material through endocytic processes, and process endocytosed proteins into peptides that can be loaded onto Major Histocompatibility Complex (MHC) molecules. In response to danger signals, DCs migrate towards lymphoid tissues where they may present MHC-bound peptides to T cells. Antigen specific CD4+ T cells are activated through peptide-carrying MHC class II molecules on DCs. Activated CD4+ T cells on their turn stimulate the proliferation and differentiation of other immune cells, including B cells, macrophages and CD8+ T cells. Cell surface expression of MHC class II by DCs is thus a critical aspect of immune regulation. One main focus of our laboratory is to delineate the molecular machineries that regulate MHC class II processing, with the ultimate goal to design more efficient vaccines and design therapies for treating immune diseases. MHC class II is constitutively synthesized and transferred to endosomes where it can be loaded with peptides from hydrolyzed endogenous proteins or exogenously acquired antigens. Whether peptide loaded MHC class II is subsequently recruited to and stably expressed at the plasma membrane or degraded in lysosomes is determined by environmental factors. We have discovered that in immature DCs, MHC class II is ubiquitinated after peptide loading, driving its sorting to the luminal vesicles of multivesicular bodies (van Niel et al 2006 Immunity). These luminal vesicles and the MHC class II they carry are delivered to lysosomes for degradation. In DCs that are activated by pathogens or inflammatory stimuli however, MHC class II is inefficiently ubiquitinated, thus allowing its transfer to and stable expression at the plasma membrane. Adaptive immunity is thus initiated through interference with ubiquitination of MHC class II. The molecular and cellular mechanisms that regulate peptide loading and ubiquitination of MHC class II, and antigen presentation to T cells are the topics of current investigations. For example, we recently collected evidence suggesting that sorting of MHC II-peptide complexes in phagosomes is autonomously controlled, and this would allow preferential stabilization of pathogen peptide loaded MHC II from phagosomes over self-peptide loaded MHC II. For our studies we make use of top of high-end technologies, including a recently acquired super resolution fluorescence microscope.
Current research group:
Esther Nolte-‘t Hoen
Toine ten Broeke
Els van der Vlist
Mieke de Boer-Brouwer
Esther van ‘t Veld
Centre for Cell Imaging
van der Vlist EJ, Nolte-’t Hoen EN, Stoorvogel W, Arkesteijn GJ, Wauben MH. Fluorescent labeling of nano-sized vesicles released by cells and subsequent quantitative and qualitative analysis by high-resolution flow cytometry. Nature Protocols 2012;7(7):1311..
ten Broeke T, van Niel G, Wauben MH, Wubbolts R, Stoorvogel W. Endosomally stored MHC class II does not contribute to antigen presentation by dendritic cells at inflammatory conditions. Traffic. 2011 12(8):1025-36.
Buschow SI, van Balkom BW, Aalberts M, Heck AJ, Wauben M, Stoorvogel W. MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis. Immunol Cell Biol. 2010 88(8):851-6.
ten Broeke T, de Graaff A, van’t Veld EM, Wauben MH, Stoorvogel W, Wubbolts R. Trafficking of MHC class II in dendritic cells is dependent on but not regulated by degradation of its associated invariant chain. Traffic. 2010 11(3):324-31.
Buschow SI, Nolte-‘t Hoen EN, van Niel G, Pols MS, ten Broeke T, Lauwen M, Ossendorp F, Melief CJ, Raposo G, Wubbolts R, Wauben MH, Stoorvogel W. MHC II in dendritic cells is targeted to lysosomes or T cell-induced exosomes via distinct multivesicular body pathways. Traffic. 2009 10(10):1528-42.
Young LJ, Wilson NS, Schnorrer P, Proietto A, ten Broeke T, Matsuki Y, Mount AM, Belz GT, O’Keeffe M, Ohmura-Hoshino M, Ishido S, Stoorvogel W, Heath WR, Shortman K, Villadangos JA. Differential MHC class II synthesis and ubiquitination confers distinct antigen-presenting properties on conventional and plasmacytoid dendritic cells. Nat Immunol. 2008 9(11):1244-52.
van Niel G, Wubbolts R, Stoorvogel W. Endosomal sorting of MHC class II determines antigen presentation by dendritic cells. Curr Opin Cell Biol. 2008 20(4):437-44.
van Niel G, Wubbolts R, Ten Broeke T, Buschow SI, Ossendorp FA, Melief CJ, Raposo G, van Balkom BW, Stoorvogel W. Dendritic cells regulate exposure of MHC class II at their plasma membrane by oligoubiquitination. Immunity. 2006 25(6):885-94.