Regulation of Immune Cell Behaviour in Complex Tissues
We are interested in understanding how immune cell function is regulated by the local tissue environment, and in particular by interactions with other cells and structures present within that environment. To achieve this, we study the migratory behaviour of immune cells in living tissues using two-photon microscopy, before defining the molecular and cellular pathways underlying this behaviour, and its contribution to the generation of a productive immune response.
For example, using a Toxoplasma gondii infection model, we have recently shown that NK cells use integrins to form close interactions with extracellular matrix structures in lymph nodes (Coombes et al, Cell reports, 2012). These interactions restrict NK cell motility, retaining them near foci of infection, where they are best placed to perform their effector function. In addition to their role in controlling infection, NK cells are an important component of the anti-tumour response. Interestingly though, NK cells often fail to penetrate the dense extracellular matrix surrounding tumours; preventing them from interacting directly with, and therefore killing, the tumour cells. Current projects in the lab are therefore focused on determining the role of integrins in regulating NK cell migration and positioning in tumours. We hope that this work will inform the design of new therapeutic strategies for optimising NK cell activity in disease.
We are also studying the interstitial migration of neutrophils, NK cells, and other immune cell populations at mucosal sites following infection.
Pathogen manipulation of host cell motility
We have recently shown that T. gondii-invaded NK cells display a hyper-motility phenotype in tissues. We now aim to understand the molecular mechanisms through which the parasite manipulates host cell migration, and whether this contributes to spread of the parasite through the host. In addition to adding to our fundamental knowledge of how NK cells migrate in tissues, this may allow us to design therapies that specifically target migration of infected host cells, thereby reducing the burden of infection.
Modelling host-pathogen interactions in 3D tissue models.
We are interested in the earliest interactions between orally acquired pathogens and the intestinal epithelium, and how this influences the development of the immune response. We are currently developing intestinal organoid models to interrogate how Toxoplasma gondii, and other protozoan parasites, interact with the host intestinal epithelium and underlying immune cell populations.
- Integrin-mediated regulation of NK cell motility and function
- A tissue slice system to determine how Toxoplasma gondii manipulates host cell motility to enhance its spread
- Optimising NK cell cytotoxicity and infiltration of the tumour microenvironment for successful adoptive immunotherapy in cancer
- Zuliza Mohamed - bench fees