Cambridge Institute for Medical Research

Professor Gillian Griffiths

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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 are very precise and efficient killers.  They are able to destroy infected or cancerous cells, without destroying healthy cells surrounding them.  The Wellcome Trust funded laboratory of Professor Gillian Griffiths investigates just how this is accomplished.  By understanding how this works, we can develop ways to control killer cells.  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.

The following video shows killer cells in action.  Insert movie 1-download from website www.vimeo.com/channels/micro

Scientific summary.

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

CTL polarize specialized secretory granules containing perforin (green) along microtubules (red) towards the immunological synapse formed with a target cell. Nuclei are blue. 

We have shown that the centrosome docks within the immunological synapse and delivers secretory granules to the precise site of secretion so that only
the target recognized is destroyed.

Two CTL attacking a target with centrosomes (red) contacting the plasma membrane at the immunological synapse formed (talin-green).

This work has also revealed striking similarities between the immunological synapse and cilia, with the centrosome docking at the site of cilia and synapse formation. 

The immunological synapse can be viewed as a “frustrated cilium”.  Centrosome docking at the plasma membrane is unusual, occurring during ciliogenesis and also during immune synapse formation. In both cases, docking of the centrosome at the plasma membrane provides a focal point for endocytosis and exocytosis.  See Journal of Cell Biology 2010 for further detail.

We aim to understand these similarities at the molecular level and are studying the role of ciliary proteins expressed by CTL in controlling polarised secretion.

Our clinical collaborations are very important in identifying proteins required for secretion and understanding how these proteins work.  Our studies have focussed on Familial Hemophagocytic Lymphohistiocytosis (FHL), a disease in which secretion of lytic proteins from CTL and NK 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 polarised secretion from these cells.

Funding

• The Wellcome Trust

Group Members

Griffiths lab members (left to right from front).  Front row: Sam Grieve, Jeansun Lee, Karen Angus.  Middle row: Maike de la Roche, Jane Stinchcombe, Yukako Asano, Roseanne Zhao, Yvonne Hackmann.   Back row: Alex Ritter and Charles Earnshaw.