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Dr Yvonne Hackmann

Research Interests

Supervisor: Professor Gillian Griffiths

Cytotoxic T-lymphocytes, or short T-cells, are crucial for the detection and clearance of virally infected and tumourigenic cells in humans.  By release of potent mediators from stored vesicles, called cytotoxic granules, T-cells specifically target and induce apoptosis of sick cells.

A number of diseases have been identified in which T-cell mediated killing is compromised, which often leads to fatal immunodeficiency.  Mutations in the SNARE protein syntaxin 11, as well as the Sec1/Munc18 protein Munc18.2 were identified as the cause of such immunodeficiencies.

My PhD focuses in understanding the role of both syntaxin11 and Munc18.2 during CTL-mediated cytotoxicity, their molecular function and how mutations occurring in patients affect that function.  By using both a biochemical and structural approach, the interaction between Stx11 and Munc18.2 is characterised in depth, focussing on how mutations in either protein compromise their respective function.  Ultimately, the aim is to embed the function of Stx11 and Munc18.2 within the general molecular machinery that is required for cytotoxic granule exocytosis and thus understand how T-cells release their cytotoxic content to destroy sick cells.  Knowledge gained from such analysis may then be applied to decide on the best choice of treatment for each individual patient and potentially even to develop novel and more potent drugs.

Keywords

SNAREs ; lytic granule secretion ; cytotoxic T cells (CTL) ; syntaxins ; Munc18.2

Topics

  • immunodeficiency

Key Publications

  1. Hackmann Y, Graham SC, Ehl S, Höning S, Lehmberg K, Aricò M, Owen DJ, Griffiths GM. Syntaxin binding mechanism and disease-causing mutations in Munc18-2. Proc Natl Acad Sci U S A. 2013 Nov 19;110(47)

    Tiziana Daniele, Yvonne Hackmann, Alex T. Ritter, Matt Wenham, Sarah Booth, Giovanna Bossi, Michael Schintler, Michaela Auer-Grumbach, Gillian M. Griffiths A Role for Rab7 in the Movement of Secretory Granules in Cytotoxic T Lymphocytes Traffic 2011 Volume 12, Issue 7, pages 902–911