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Gillian Griffiths

Control of secretion at the immunological synapse

Cells of the immune system protect the body against pathogens. If cells in our bodies are infected by viruses, or become cancerous, then killer cells of the immune system identify and destroy the affected cells. Cytotoxic T cells (CTLs) are very precise and efficient killers. They are able to destroy infected or cancerous cells, without destroying healthy cells surrounding them. We aim to uncover the mechanisms controlling secretion from CTL and natural killer (NK) cells. By understanding how this works, we can develop ways to control the 'killer' cells of the immune system. This will allow us to find ways to improve cancer therapies, and ameliorate autoimmune diseases caused when killer cells run amok and attack healthy cells in our bodies.

Our laboratory is interested in understanding the mechanisms that control polarized secretion from cytotoxic T lymphocytes  and NK cells. We use cutting-edge imaging, molecular, genetic and biochemical techniques to identify the proteins required for polarized secretion, and to understand the way in which they work.

Using imaging we can see the directed movement of secretory granules (red) as the killer cell (labelled with actin in green) polarizes towards the target (blue):

T cell killing Griffiths lab

We use 3D live imaging in order to capture events across the cell:


We discovered that the centrosome docks at the immunological synapse and delivers secretory granules to the precise site of secretion so that only the target is destroyed. Centrosome docking at the plasma membrane is very unusual, occurring during cilia formation, and our work has revealed striking similarities between the immunological synapse and cilia formation:

Griffiths cilia graphic

Most recently, we have extended these findings to show that Hedgehog signalling 'pre-arms' CTLs for the centrosome polarization that is required for granule delivery (de la Roche et al. Science 2013).

Clinical collaborations have a very important role in identifying proteins required for secretion and understanding how these proteins work. Our studies have focused on Familial Hemophagocytic Lymphohistiocytosis (FHL), a disease in which secretion of lytic proteins from CTLs and NK cells is disrupted, and the cells fail to kill. Loss of perforin, Rab27a, Munc13-4, 18-2 and syntaxin 11 all lead to loss of CTL secretion and we wish to determine the interactions that allow these proteins to control polarized secretion from these cells. Our studies have allowed us to understand these interactions at the molecular level and revealed a chaperone role for Munc 18-2 in delivering syntaxin 11 to the plasma membrane (Hackmann et al. PNAS 2013).

An exciting new area in the lab is our part in the Infection, Immunity and Immunophenotyping (3i) consortium with the Wellcome Trust Sanger Institute, Kings College London, Oxford and Manchester. Our lab is screening all mutations for loss of CTL secretion, with data being made available through the WTSI website.

Griffiths lab 2018


Key papers:

Ma, C, Marioni, J, Griffiths, GM and Richard, A. Stimulation strength controls the rate of initiation but not the molecular organization of TCR-induced signalling. eLife, 9:e53948. doi: 10.7554/eLife.53948 (2020).

Randzavola LO, Strege K, Juzans M, Asano Y, Stinchcombe JC, Gawden-Bone CM, Seaman MNJ, Kuijpers T. and Griffiths GM. Loss of ARPC1B impairs cytotoxic T lymphocyte maintenance and cytolytic activity. Journal of Clinical Investigation, 129(12), pp.5600-5614 (2019).

Ritter AT, Kapnick SM, Murugesan S, Schwartzberg PL, Griffiths GM, Lippincott-Schwartz J. Cortical actin recovery at the immunological synapse leads to termination of lytic granule secretion in cytotoxic T lymphocytes. Proc. Natl Acad. Sci. USA 114(32):E6585-E6594. doi: 10.1073/pnas.1710751114 (2017).

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).

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).


Gillian Griffiths


Gillian Griffiths

Professor of Immunology and Cell Biology, FRS

Department of Medicine

Contact details:

01223 763342

Plain English

Our immune system ensures that our body remains healthy despite continual invasion by bacteria and viruses. We are particularly interested in the function of T cells, which seek out and destroy virally infected cells and tumour cells. The incredible ability of T cells to recognize a target and rapidly destroy it relies on the formation of a special contact or 'synapse' with the target which is initiated at the right place by the movement of a cell structure termed the centrosome. We use microscopy to track this process in fine detail and so map the events that control synapse formation. We also investigate the protein signals that direct these changes, and this has important implications for understanding how the immune system works to fight infection, and how immune diseases can arise.



Group members

Yukako Asano · Tiphaine Douanne · Philippa Barton · Miriam Lisci · Anna Lippert · Claire Ma · Arianne Richard · Jane Stinchcombe · Carla Vazquez Amos




Wellcome Trust