Director of Cambridge Institute for Medical Research
Gillian Griffiths is interested in taking PhD students.
Gillian Griffiths is available for consultancy.
Control of Secretion at the Immunological Synapse
Cells of the immune system need to communicate in order to co-ordinate an effective immune response. The immunological synapse formed between effector cells and their antigen-presenting cells provides a mechanism for directed communication, either via cell surface receptors or secreted proteins. Secretion is focused within the synapse: in the case of cytotoxic T lymphocytes (CTL) this is essential so that only the infected target is destroyed.
My lab studies the mechanisms that control secretion within the immunological synapse using a range of functional, biochemical and imaging techniques. We have close clinical collaborations that allow us to study CTL from patients with genetic diseases (e.g. Haemophagocytic Lymphohistiocytosis) that disrupt secretion at the immunological synapse, and thereby identify the machinery required for granule delivery and fusion at the synapse as well as providing a better understanding of the genetic disease.
We have discovered that CTL and NK cells use a novel secretory mechanism, with the centrosome polarizing to the precise site of secretion within the immunological synapse. This mechanism, that requires the centrosome to dock at the plasma membrane, bears striking similarities to cilia formation, with endocytosis and exocytosis focused at the point of centrosome docking in both. We are currently exploring the molecular similarities between cilia and synapse formation using genetic, morphological and functional studies.
CTL provide an excellent model for understanding the mechanisms that control centrosome polarization, and we have exploited genetic models in which components of the T cell receptor signaling pathway can be turned off. A key aspect to all of these studies is the use of live imaging to follow synapse formation and secretion in real time, and dissect out the delivery of the secretory machinery to the immunological synapse.
NK ; perforin ; cell surface molecules ; human studies ; immune synapse ; cytotoxic T cells (CTL) ; granzyme ; secretory lysosome ; CTL ; natural killer cells
Maike de la Roche, Alex T. Ritter, Karen L. Angus, Colin Dinsmore, Charles H. Earnshaw, Jeremy F. Reiter, and Gillian M. Griffiths. Hedgehog Signaling Controls T Cell Killing at the Immunological Synapse. Science 6 December 2013: 1247-1250.
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)
Griffiths GM. Open questions: missing pieces from the immunological jigsaw puzzle. BMC Biol. 2013 Jan 31;11:10. doi: 10.1186/1741-7007-11-10.
Angus KL, Griffiths GM. Cell polarisation and the immunological synapse. Curr Opin Cell Biol. 2012 Sep 15.
Lui-Roberts WW, Stinchcombe JC, Ritter AT, Akhmanova A, Karakesisoglou I, Griffiths GM. Cytotoxic T lymphocyte effector function is independent of nucleus-centrosome dissociation. Eur J Immunol. 2012 Aug;42(8):2132-41.
Tsun, A., Qureshi, I., Stinchcombe, J. C., Jenkins, M. R., de la Roche, M., Kleczkowska, J., Zamoyska, R. and Griffiths, G. M. Centrosome docking at the immunological synapse is controlled by Lck signaling. J Cell Biol 2011192, 663-674.
Daniele, T., Hackmann, Y., Ritter, A. T., Wenham, M., Booth, S., Bossi, G., Schintler, M., Auer-Grumbach, M. and Griffiths, G. M. A role for rab7 in the movement of secretory granules in cytotoxic T lymphocytes. Traffic 2011 12, 902-911.
Stinchcombe JC, Salio M, Cerundolo V, Pende D, Arico M, Griffiths GM. Centriole polarisation to the immunological synapse directs secretion from cytolytic cells of both the innate and adaptive immune systems. BMC Biol. 2011 Jun 28;9:45.
Griffiths, G. M., Tsun, A. and Stinchcombe, J. C. The immunological synapse: a focal point for endocytosis and exocytosis. J Cell Biol 2010 189, 399-406.