School of Biomedical Sciences - Research Publications

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Author: Mintern, Justine × Author: Caminschi, Irina ×

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    The Dendritic Cell Receptor Clec9A Binds Damaged Cells via Exposed Actin Filaments
    Zhang, J-G ; Czabotar, PE ; Policheni, AN ; Caminschi, I ; Wan, SS ; Kitsoulis, S ; Tullett, KM ; Robin, AY ; Brammananth, R ; van Delft, MF ; Lu, J ; O'Reilly, LA ; Josefsson, EC ; Kile, BT ; Chin, WJ ; Mintern, JD ; Olshina, MA ; Wong, W ; Baum, J ; Wright, MD ; Huang, DCS ; Mohandas, N ; Coppel, RL ; Colman, PM ; Nicola, NA ; Shortman, K ; Lahoud, MH (CELL PRESS, 2012-04-20)
    The immune system must distinguish viable cells from cells damaged by physical and infective processes. The damaged cell-recognition molecule Clec9A is expressed on the surface of the mouse and human dendritic cell subsets specialized for the uptake and processing of material from dead cells. Clec9A recognizes a conserved component within nucleated and nonnucleated cells, exposed when cell membranes are damaged. We have identified this Clec9A ligand as a filamentous form of actin in association with particular actin-binding domains of cytoskeletal proteins. We have determined the crystal structure of the human CLEC9A C-type lectin domain and propose a functional dimeric structure with conserved tryptophans in the ligand recognition site. Mutation of these residues ablated CLEC9A binding to damaged cells and to the isolated ligand complexes. We propose that Clec9A provides targeted recruitment of the adaptive immune system during infection and can also be utilized to enhance immune responses generated by vaccines.
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    Targeting antigen to bone marrow stromal cell-2 expressed by conventional and plasmacytoid dendritic cells elicits efficient antigen presentation
    Moffat, JM ; Segura, E ; Khoury, G ; Caminschi, I ; Cameron, PU ; Lewin, SR ; Villadangos, JA ; Mintern, JD (WILEY-BLACKWELL, 2013-03-01)
    Bone marrow stromal cell-2 (BST-2) has major roles in viral tethering and modulation of interferon production. Here we investigate BST-2 as a receptor for the delivery of antigen to dendritic cells (DCs). We show that BST-2 is expressed by a panel of mouse and human DC subsets, particularly under inflammatory conditions. The outcome of delivering antigen to BST-2 expressed by steady state and activated plasmacytoid DC (pDC) or conventional CD8(+) and CD8(-) DCs was determined. T-cell responses were measured for both MHC class I (MHCI) and MHC class II (MHCII) antigen presentation pathways in vitro. Delivering antigen via BST-2 was compared with that via receptors DEC205 or Siglec-H. We show that despite a higher antigen load and faster receptor internalisation, when antigen is delivered to steady state or activated pDC via BST-2, BST-2-targeted activated conventional DCs present antigen more efficiently. Relative to DEC205, BST-2 was inferior in its capacity to deliver antigen to the MHCI cross-presentation pathway. In contrast, BST-2 was superior to Siglec-H at initiating either MHCI or MHCII antigen presentation. In summary, BST-2 is a useful receptor to target with antigen, given its broad expression pattern and ability to access both MHCI and MHCII presentation pathways with relative efficiency.
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    Criteria for Dendritic Cell Receptor Selection for Efficient Antibody-Targeted Vaccination
    Reuter, A ; Panozza, SE ; Macri, C ; Dumont, C ; Li, J ; Liu, H ; Segura, E ; Vega-Ramos, J ; Gupta, N ; Caminschi, I ; Villadangos, JA ; Johnston, APR ; Mintern, JD (AMER ASSOC IMMUNOLOGISTS, 2015-03-15)
    Ab-targeted vaccination involves targeting a receptor of choice expressed by dendritic cells (DCs) with Ag-coupled Abs. Currently, there is little consensus as to which criteria determine receptor selection to ensure superior Ag presentation and immunity. In this study, we investigated parameters of DC receptor internalization and determined how they impact Ag presentation outcomes. First, using mixed bone marrow chimeras, we established that Ag-targeted, but not nontargeted, DCs are responsible for Ag presentation in settings of Ab-targeted vaccination in vivo. Next, we analyzed parameters of DEC205 (CD205), Clec9A, CD11c, CD11b, and CD40 endocytosis and obtained quantitative measurements of internalization speed, surface turnover, and delivered Ag load. Exploiting these parameters in MHC class I (MHC I) and MHC class II (MHC II) Ag presentation assays, we showed that receptor expression level, proportion of surface turnover, or speed of receptor internalization did not impact MHC I or MHC II Ag presentation efficiency. Furthermore, the Ag load delivered to DCs did not correlate with the efficiency of MHC I or MHC II Ag presentation. In contrast, targeting Ag to CD8(+) or CD8(-) DCs enhanced MHC I or MHC II Ag presentation, respectively. Therefore, receptor expression levels, speed of internalization, and/or the amount of Ag delivered can be excluded as major determinants that dictate Ag presentation efficiency in setting of Ab-targeted vaccination.