Director of Cambridge Institute for Medical Research
Gillian Griffiths is accepting applications for PhD students.
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
Dieckmann Nele M G, Frazer Gordon L, Asano Yukako, Stinchcombe Jane C, Griffiths Gillian M, The cytotoxic T lymphocyte immune synapse at a glance. J Cell Sci 129(15):2881-2886 (2016) PMID 27505426
De la Roche M, Asano Y, Griffiths GM, Origins of the cytolytic synapse. Nat Rev Immunol 16(7):421-432 (2016) PMID 27265595
Ammann S, Schulz A, Krägeloh-Mann I,Dieckmann NMG, Niethammer K, Fuchs S, Eckl KM, Plank R, Werner R, Altmüller J, Thiele H, Nürnberg P, Bank J, Strauss A, Von Bernuth H, Zur Stadt U, Grieve S, Griffiths GM, Lehmberg K, Hennies HC & Ehl S. Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome. Blood 127, 997–1006 (2016). PMID 26744459
Stinchcombe JC, Randzavola L, Angus KL, Mantell JM, Verkade P & Griffiths GM. Mother Centriole Distal Appendages Mediate Centrosome Docking at the Immunological Synapse and Reveal Mechanistic Parallels with Ciliogenesis. Current Biol. 25, 3239–3244 (2015).
Dieckmann NMG, Hackmann Y, Aricò M & Griffiths GM. Munc18-2 is required for Syntaxin 11 Localization on the Plasma Membrane in Cytotoxic T-Lymphocytes. Traffic 16, 1330–1341 (2015).
Ritter AT, Asano Y, Stinchcombe JC, Dieckmann NM, Chen BC, Gawden-Bone C, van Engelenburg S, Legant W, Gao L, Davidson MW, Betzig E, Lippincott-Schwartz J, Griffiths GM. Actin depletion initiates events leading to granule secretion at the immunological synapse. Immunity 42, 864-876. doi: 10.1016/j.immuni.2015.04.013 (2015).
Jenkins, M. R. et al. Distinct structural and catalytic roles for Zap70 in formation of the immunological synapse in CTL. eLife 3:e01310 (2014).
de la Roche, M. et al. Hedgehog signaling controls T-cell killing at the immunological synapse. Science 342, 1247–1250 (2013).
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)