Prof Dan Davis

Dan Davis – Research summary

Dan Davis

Dan Davis

The supramolecular dynamics of human immune cell recognition and communication

Signal integration

Cell-contact dependent regulation of immune cell responses plays a vital role in balancing the need for rapid and efficient responses to a wide variety of pathological challenges, while at the same time maintaining self-tolerance. The principal cell surface molecules involved in such immune cell interactions have been identified and where and when each protein-protein interaction occurs to regulate cell functions remains a central gap in our understanding of how signals are integrated and how immune responses are regulated. Over the last decade, much research has studied how immune cell interactions are often accompanied by the segregation of proteins into micrometer- and submicrometer-scale domains at an immune synapse. Through recent improvements in imaging technology, it has now been established that within immune synapses, kinases, adaptors, and antigen receptors accumulate within structures termed microclusters. T cell receptor signalling, for example, is initiated in such microclusters and these signals are terminated as microclusters move from the periphery to the centre of the synapse. In Natural Killer (NK) cells, phosphorylation of inhibitory Killer Ig-like receptors (KIR) is restricted to microclusters (Treanor, Lanigan et al. 2006) indicating that inhibitory signalling is also spatially restricted. Moreover, very recent data using new super-resolution microscopy has revealed that microclusters themselves are structured (Lillemeier, Mortelmaier et al.) . Although this is very little understood in terms of specific mechanisms and functions, the emerging new paradigm is that interactions between immune cell receptors, kinases and adaptors are at least in part controlled by the dynamics of supramolecular assemblies. Hence, immune cell recognition and signalling is governed by transient interactions between heterogeneous clusters of proteins. This is a substantially different concept from a linear cascade of individual protein-protein interactions that is always depicted in textbook diagrams of immune receptor signalling pathways. Thus, the major new challenge tackled by my laboratory is to determine how the heterogeneity and single-molecule level organisation of protein clusters influences NK cell signal integration and downstream effector functions.

Nanotubes

Another new concept that has directly arisen from imaging immune cell interactions is that long membrane tethers or membrane nanotubes can sustain direct physical connections between immune cells and other cells over long distances. Membrane nanotubes can vary in specific structure, process of formation and functional properties. Nanotubes can traffic vesicles (Onfelt, Nedvetzki et al. 2006) or transmit calcium-mediated signals and can contribute to pathologies, e.g. by directing the spread of viruses or prions. Our very recent data has revealed that NK cell nanotubes contain a sub-micrometer scale immune synapse. Functionally, we have found that nanotubes can aid cell-mediated killing of distant target cells, either directly or by bringing target cells back into close contact for killing via a conventional (i.e. large) immune synapse. These data open a new avenue for research in immune cell biology since, while synaptic communication over long distances is well-established as being important for cells in the nervous system, this is a new proposition for immune cells. Again, little is understood in the details and further work is sorely needed to understand what traffics within nanotubes, what signals could emanate from nanotube synapses, and what may perturb nanotube existence, structure and function. In the longer term, this may well identify novel therapeutic targets since intervention in nanotube stability or function could influence intercellular transmission of viruses such as HIV-1 or abrogate immune responses such as unwanted cytotoxcity in auto-immune diseases.

Super-resolution imaging

The major bottleneck for advancing research in membrane nanotubes is that they are ~300 nm in diameter and therefore at the limit of detection by conventional light microscopy. Similarly, the principal bottleneck in studying synapse structure and function is proteins are clearly organised and interact dynamically on a sub-micron scale. Crucially, the diffraction-limit for the spatial resolution of light microscopy has been circumvented through a variety of complementary techniques, collectively known as super-resolution microscopy. These new advances in technology provide an exciting window of opportunity for understanding molecular recognition by immune cells, both in probing the organisation, heterogeneity, and interactions between protein clusters at immune synapses, and for probing mechanisms and functions for membrane nanotubes.

Intercellular transfer of proteins and RNA

Our own data, and a couple of very recent publications from others, indicate that RNA can traffic between cells. This implicates a new and unexpected mechanism by which cells interact with each other, which could be very important in understanding and treating a range of diseases. Thus, exploiting and expanding the experience I have gained in previously studying intercellular protein transfer, I now aim to explore functions and mechanisms for intercellular transfer of RNA.

People

Dan Davis – People

Dr Stefan Balint
Charlotte Barthen
Adam Cartwright
Karoliina Tuomela Inés Díaz Del Olmo
Mr Daniel Friedman
Alexandros Karampatzakis
Dr Philippa Kennedy
Kathryn Lagrue
Dr David Morgan
Anna Oszmiana
Kevin Stacey
Poppy Simmonds
Ms Katja Srpan
Ms Mezida Bedru Saeed
Ms Katherine Walwyn-Brown
Dr David Williamson

People

Dan Davis – People

Dr Stefan Balint
Charlotte Barthen
Adam Cartwright
Karoliina Tuomela Inés Díaz Del Olmo
Mr Daniel Friedman
Alexandros Karampatzakis
Dr Philippa Kennedy
Kathryn Lagrue
Dr David Morgan
Anna Oszmiana
Kevin Stacey
Poppy Simmonds
Ms Katja Srpan
Ms Mezida Bedru Saeed
Ms Katherine Walwyn-Brown
Dr David Williamson

Collaborators

Jeremy Griggs - GSK
Matthew Sleeman - MedImmune/AstraZeneca
Paul French - Imperial College London
Rajesh Chopra - Celgene

Biography

Daniel M Davis, PhD, is The Director of Research in the Manchester Collaborative Centre for Inflammation Research. Prior to this, he was a Professor of Molecular Immunology at Imperial College London, UK and Head of the Immunology and Infection Section at the South Kensington Campus. He previously completed an Irvington Institute Postdoctoral Fellowship with Professor Jack Strominger at Harvard University, Cambridge, MA, USA, after earning a PhD in Physics at Strathclyde University, Glasgow, UK, and a BSc in Physics at the University of Manchester, UK.

Professor Davis pioneered the use of novel imaging techniques to help visualize key molecular components of the immune response. His work helped establish new concept of how immune cells communicate with each other and how they recognize disease. In 1999, he published the first images showing protein reorganisation at the interface between human Natural Killer (NK) cells and tumour cells. Exploring how changes in the arrangements of proteins occur and how they control communication between immune cells established the concept of the immune synapse, now recognised for its critical importance in cell communication and viral transfer between cells.

His group also described long membrane tethers or ‘nanotubes’ as a new class of physical connectors between immune cells ,which have now been visualised in vivo as well as in vitro. Such membrane nanotubes aid immune cell activity and present a novel direct route for HIV-1 to efficiently spread between T cells.

Professor Davis has published over 100 papers, collectively cited more than 6000 times, and was the recipient of a Lister Prize Fellowship in 2005, a Wolfson Royal Society Merit Award in 2008 and became a Fellow of the Academy of Medical Sciences in 2011. He has authored many articles for a general audience, has presented several, well-received public lectures, and is currently writing a popular-level science book – The Compatibility Gene - to be published by Penguin in 2013.

Publications

  • Davis D.M., Chiu I., Fassett M., Cohen G.B., Mandelboim O., Strominger J.L. The human natural killer cell immune synapse, Proc. Natl. Acad. Sci., 96, (1999), 15062-15067.
  • Carlin L.M., Eleme K., McCann F., Davis D.M., Intercellular transfer and supramolecular organization of human leukocyte antigen C at inhibitory Natural Killer cell immune synapses. J. Exp. Med., 194, (2001), 1507-1517.
  • Eleme K., Taner S.B., önfelt B., Collinson L.M., McCann F.E., Chalupny N.J., Cosman D., Hopkins C., Magee A.I., Davis D.M., Cell surface organization of stress-inducible proteins ULBP and MICA that stimulate human NK cells and T cells via NKG2D, J. Exp. Med., 199, (2004), 1005-1010.
  • Davis D.M., Dustin M.L., What is the importance of the immunological synapse?, Trends Immunol., 25, (2004), 323-327 Önfelt B., Nedvetzki S., Yanagi K., Davis D.M., Cutting Edge: Membrane nanotubes connect immune cells, J. Immunol., 173, (2004), 1511-1513.
  • Treanor B., Lanigan P.M.P., Kumar S., Dunsby C., Munro I., Auksorius E., Culley F.J., Purbhoo M.A., Phillips D., Neil M.A.A., Burshtyn D.N., French P.M.W., Davis D.M. Microclusters of inhibitory Killer Immunologlobulin-like Receptor signaling at Natural Killer cell immunological synapses, J. Cell Biol., 174, (2006), 153-161.
  • Davis D.M., Intercellular transfer of cell surface proteins is common and can impact many stages of an immune response, Nat Rev Immunol, 7, (2007), 238-243.
  • Nedvetzki S., Sowinski S., Harris J., Eagle R.A., Vély F., Pende D., Trowsdale J., Vivier E., Gordon S., Davis D.M., Reciprocal regulation of Natural Killer cells and macrophages associated with distinct immune synapses, Blood, 109, (2007), 3776-85.
  • Sowinski S., Jolly C., Berninghausen O., Purbhoo M.A., Chauveau A., Köhler K., Oddos S., Eissmann P., Brodksy F.M., Hopkins C., Önfelt B., Sattentau Q., Davis D.M., Membrane nanotubes physically connect T cells over long distances presenting a novel route for HIV transmission, Nat Cell Biol, 10, (2008), 211-219.
  • Culley F.J, Johnson M., Evans H.J., Kumar S., Crilly R., Casasbuenas J., Schnyder T., Mehrabi M., Deonarain M.P., Ushakov D.S., Braud V., Roth G., Brock R., Köhler K., Davis D.M., Natural Killer cell signal integration balances synapse symmetry and migration, PLoS Biol, 7, (2009), e1000159.
  • Chauveau A., Aucher A., Eissmann P., Vivier E., Davis D.M., Membrane nanotubes facilitate long distance interactions between Natural Killer cells and target cells, Proc. Natl. Acad Sci, 107, (2010), 5545-5550.
  • Purbhoo M.A., Liu H., Owen D.M., Oddos S., Neil M.A.A., Pageon S.V., French P.M.W., Rudd C.E., Davis D.M., Dynamic interactions between sub-synaptic vesicles and surface microclusters at the immunological synapse, Science Signaling, 3, ra36, (2010).
  • Brown A.C.N., Oddos S., Dobbie I.M., Alakoskela J.-M., Parton R.M., Eissmann P., Neil M.A.A., Dunsby C., French P.M.W., Davis I., Davis D.M., Remodelling of Cortical Actin Where Lytic Granules Dock at Natural Killer Cell Immune Synapses Revealed by Super-Resolution Microscopy, PLoS Biology,. 9(9):e1001152, (2011).
  • Brown A.C., Dobbie I.M., Alakoskela J.M., Davis I., Davis D.M. Super-resolution imaging of remodelled synaptic actin reveals different synergies between NK cell receptors and integrins. Blood, 20, 3729-40, (2012).