The supramolecular dynamics of human immune cell recognition and communication

Lead Research Organisation: University of Manchester
Department Name: School of Medical Sciences

Abstract

We have given names to nearly all the different protein molecules that mediate communication between human cells. Now, the audacious goal of contemporary cell biology is to understand how the billion proteins in an average cell allow them to move, multiply, create a brain or defend us against viruses and bacteria. Imaging where and when proteins interact with each other has a major role to play at this frontier. Recent imaging of just a few types of proteins has already led to important new concepts in how immune cells communicate with each other and how they recognize signs of disease. Images of immune cells contacting other cells have revealed temporary membrane structures, often called immune synapses, similar to the synapses that nerve cells make with one another for communication. Exploring how such changing arrangements of proteins occur and how they control immune cell communication is the new science opened up by the immune synapse concept.
My research team and others have also very recently observed that long tubes, made of cell membrane, readily form between immune cells. We called these connections membrane nanotubes and they could constitute a new mechanism for communication between cells that are far apart. A cost, however, is that viruses such as HIV may use these connections to efficiently spread between cells. Thus, we aim to determine how these connections form and what functional consequences they have for the human immune system.
We have also observed that RNA can traffic between cells suggesting a new and unexpected mechanism by which cells interact with each other. This could be very important in understanding and treating a range of diseases and we aim here to determine mechanisms and functions for this phenomenon.
Studying these new phenomena can seed important new research areas for how cell-cell interactions lead to effective immune surveillance of tumours and viral-infected cells. Many of the specific examples studied in my laboratory have clear medical importance. For example, studying interactions between macrophages and Natural Killer cells is likely to prove relevant in understanding the underlying causes of sepsis. Also, to realize the proposed experiments we will exploit new imaging technologies, which will be of broad interest across several biological research fields and patents may be sought upon development of specific applications. Excitingly, high-resolution microscopy of immune cell interactions is still a very young field and more surprises are surely in store.

Technical Summary

The key focus of my research over recent years has been the successful combination of addressing important problems in cell biology and immunology with novel and state-of-the-art photonics technology. Our imaging studies have helped establish an emerging new paradigm that interactions between immune cell receptors, kinases and adaptors are at least in part controlled by the dynamics of supramolecular assemblies. Thus, immune cell recognition and signalling is governed by transient interactions between heterogeneous clusters of proteins, a substantially different concept from the linear cascade of individual protein-protein interactions depicted in textbooks. Thus, the new challenge presented here is to assess the heterogeneity and single-molecule level organisation of protein clusters and understand how this influences signal integration and downstream effecter functions. Addressing this major gap in NK cell biology, and immune cell biology in general, necessitates the application of new super-resolution imaging techniques. Thus, we will engineer a range of specific cellular interactions and apply super-resolved imaging techniques, including STORM and PALM, which will permit step changes in the speed, resolution and level of quantification. We will compare the dynamic organisation of the NK cell synapse when the overall signalling is tipped towards inhibition or activation. Also, we will use photocleavable peptides able to trigger NK cell inhibition upon activation to determine the timing of NK cell signal integration in relation to interactions and dynamics of NK cell microclusters.
In addition, we have recently presented evidence that intercellular membrane nanotubes connecting a wide variety of immune cells can aid functions such as NK cell-mediated cytotoxicity and can be exploited by pathogens, such as for the spread of HIV-1 between T cells. Thus, membrane nanotubes represent a new research area which may be important across many biological systems both in health and disease. Using a combination of state-of-the-art and novel imaging techniques, we now propose to compare and contrast the molecular structure of nanotubes between different cell types and test specific functions for nanotubes including aiding cell-mediated cytotoxicity and communication via sub-micronscale nanotube synapses.
Finally, we will also establish a new line of research to investigate intercellular transfer of RNA. We will determine which types of RNA transfer and probe the mechanism for RNA transfer. We will test for specific functional consequences of RNA transfer, including that it could be the basis for a novel viral evasion strategy and/or a new way by which cells communicate with each other.

Publications

10 25 50
 
Title Book: The Compatibility Gene 
Description The Compatibility Gene is a scientific adventure story set in a new field of genetic discovery - that of the crucial genes that define our relationships, our health and our individuality. Here, Daniel M Davis, one of the leading scientists in the field, tells us the story of its grounbreaking developments that have the potential to change us all We each possess a similar set of around 25,000 human genes. Yet a tiny, distinctive cluster of these genes plays a disproportionately large part in how our bodies work. These few genes, argues Daniel M. Davis, hold the key to who we are as individuals and our relationship to the world: how we combat disease, how our brains are wired, how attractive we are, even how likely we are to reproduce. In The Compatibility Gene, one of our foremost immunologists tells the remarkable history of these genes' discovery and the unlocking of their secrets. From the British scientific pioneers who, during the Second World War, struggled to understand the mysteries of transplants and grafts, to the Swiss zoologist who devised an entirely new method of assessing potential couples' compatibility based on the smell of worn T-shirts, Davis traces what is nothing less than a scientific revolution in our understanding of the human body: a global adventure spanning some sixty years. Davis shows how the compatibility gene is radically transforming our knowledge of the way our bodies work - and is having profound consequences for medical research and ethics. Looking to the future, he considers the startling possibilities of what these wondrous discoveries might mean for you and me. 
Type Of Art Creative Writing 
Year Produced 2014 
Impact The Compatibility Gene was longlisted for the 2014 Royal Society Winton Science Book Prize, short-listed for the Society of Biology book prize and received a series of outstanding reviews in The Times, New York Times, Guardian, New Scientist, New Statesman, BBC Focus, Nature and so on. It was picked by Bill Bryson for the Guardian's Books of the Year feature 2013 and was included in Nature's features on Summer Books 2014 and Autumn Books 2014. A humorous piece by the popular journalist Tim Dowling, highlighted The Compatibility Gene on the front cover of The Guardian (8th Sept 2013) and featured in Dowling's own book How to be a Husband (2014). Davis discussed The Compatibility Gene on BBC Breakfast TV, as well as on US TV (The Circle, MS-NBC), the Guardian science podcast and several radio stations. Nature profiled Davis twice in 2013; in a feature on scientists who write books (Get the word out) and for his research discoveries. He has published articles in Scientific American, BBC Focus magazine, Physics World and previously won the Oxford University Press Science Writing Prize. In 2014, Davis presented The Compatibility Gene at the Hay Festival (Wales stage; 700 attendees), The Royal Institution in London (400 attendees), Edinburgh Science Festival, Manchester Science Festival, York's Festival of Ideas, Latitude music festival and many other events. 
URL http://www.amazon.co.uk/The-Compatibility-Gene-Daniel-Davis/dp/1846145147/ref=tmm_hrd_title_0
 
Description MRC program grant renewal
Amount £1,821,556 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2011 
End 10/2016
 
Description Manchester Collaborative Centre
Amount £2,000,000 (GBP)
Organisation University of Manchester 
Department Manchester Collaborative Centre for Inflammation Research (MCCIR)
Sector Academic/University
Country United Kingdom
Start 11/2012 
End 10/2017
 
Description Wellcome Trust Investigator award
Amount £1,800,000 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Bloomsbury Centre
Sector Charity/Non Profit
Country United Kingdom
Start 10/2016 
End 10/2021
 
Title New imaging technologies have been developed 
Description new approaches to imaging immune cell activation have been developed 
Type Of Material Improvements to research infrastructure 
Provided To Others? No  
Impact Several labs world-wide have taken up some of the new imaging approaches we have developed 
 
Title Nk cell and 221 transfectants 
Description Several cell line transfectants were made and these have been distributed to many labs in several countries. 
Type Of Material Cell line 
Year Produced 2009 
Provided To Others? Yes  
Impact Several cell line transfectants were made and these have been distributed to many labs in several countries. 
 
Description Collaboration with MedImmune 
Organisation MedImmune
Department Infection
Country United States 
Sector Private 
PI Contribution The project is entirely collaborative with this company
Collaborator Contribution Many reagents are being made in this company for our research
Impact We hope to determine the best approach for antibody-based drugs that work through ADCC
Start Year 2010
 
Description Communicating complex network information by intercellular transfer of macrophage proteins and RNA 
Organisation Merck
Country Germany 
Sector Private 
PI Contribution Communicating complex network information by intercellular transfer of macrophage proteins and RNA
Collaborator Contribution Communicating complex network information by intercellular transfer of macrophage proteins and RNA
Impact Communicating complex network information by intercellular transfer of macrophage proteins and RNA
Start Year 2008
 
Description Understanding and manipulating Antibody Dependent Cell Cytotoxicity (ADCC) by human Natural Killer (NK) cells 
Organisation MedImmune
Country United States 
Sector Private 
PI Contribution This is a new grant funded by the MRC in collaboration with the company MedImmune
Collaborator Contribution Reagents and expertise is provided.
Impact This is a new funded grant, work is just now beginning. In addition, a postdoc from my lab will take up a new permanent post at this company
Start Year 2009
 
Description Popular Science Book 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The Compatibility Gene was longlisted for the 2014 Royal Society Winton Science Book Prize, short-listed for the Society of Biology book prize and received a series of outstanding reviews in The Times, New York Times, Guardian, New Scientist, New Statesman, BBC Focus, Nature and so on. It was picked by Bill Bryson for the Guardian's Books of the Year feature 2013 and was included in Nature's features on Summer Books 2014 and Autumn Books 2014. A humorous piece by the popular journalist Tim Dowling, highlighted The Compatibility Gene on the front cover of The Guardian (8th Sept 2013) and featured in Dowling's own book How to be a Husband (2014).

Public awareness of immunology. This lead to extensive interantional coverage including TV appearences in the UK and USA, tens of radio interviews and my book received superb reviews in The New York Times, The Times, The Guardian, New Scientist and many many other places.
Year(s) Of Engagement Activity 2012
URL http://www.amazon.co.uk/The-Compatibility-Gene-Daniel-Davis/dp/1846145147/
 
Description Public Lectures / Interviews 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Davis discussed The Compatibility Gene on BBC Breakfast TV, as well as on US TV (The Circle, MS-NBC), the Guardian science podcast and several radio stations. Nature profiled Davis twice in 2013; in a feature on scientists who write books (Get the word out) and for his research discoveries. He has published articles in Scientific American, BBC Focus magazine, Physics World and previously won the Oxford University Press Science Writing Prize. In 2014, Davis presented The Compatibility Gene at the Hay Festival (Wales stage; 700 attendees), The Royal Institution in London (400 attendees), Edinburgh Science Festival, Manchester Science Festival, York's Festival of Ideas, Latitude music festival and many other events.

Public lectures were extremely well attended
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
URL http://www.davislab.ls.manchester.ac.uk/book/articlesandvideos/
 
Description Science Museum talks 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact As one example of my public talks, I gave two talks at The Science Museum, London, on the immune system as part of their Lates event on Feb 24th 2016.
Year(s) Of Engagement Activity 2016
 
Description Scientific American article 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I published a major article in this research area in Scientific American magazine which has a worldwide subscription of over one million.

This was the most downloaded article at the time of publication
Year(s) Of Engagement Activity 2006
 
Description Summary of media activities 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Davis keenly engages in making immunology accessible to non-specialist audiences. In August 2013, his popular-level book about the immune system entitled The Compatibility Gene was published by Penguin. The book received praise from Steven Pinker (Harvard), Steve Jones (UCL), Armand Leroi (Imperial) and Peter Doherty (Nobel Laureate), and had fantastic reviews, including in The Times, New York Times, Guardian, New Scientist, New Statesman, BBC Focus and Nature. It was picked by Bill Bryson in the Guardian's Books of the Year feature. An article about the book was also written by the popular journalist Tim Dowling, highlighted on the front cover of the Guardian (8th Sept 2013), and was discussed by comedian Russell Brand. The book and these articles also brought awareness to Anthony Nolan, the bone marrow transplantation charity.
In 2013, Davis discussed the immune system and genetics with Bill Turnbull and Susannah Reid on BBC Breakfast TV, watched by over 1 million, and also on live US TV on The Circle, MSNBC. In 2013, Davis did over 15 radio interviews including several BBC radio stations, NPR California and Radio New Zealand. The Smithsonian Institute (USA) published a profile of Davis in 2013 and Nature magazine also profiled Davis in its feature on scientists who write books (Get the word out, Nature, 504, 177-179, 2013).
In 2006, Davis published a major article - Secrets of the Immune Synapse - in Scientific American magazine, which has a worldwide readership of 1 million. In 2014, he published an article on the frontiers of immunology in BBC Focus magazine. He has been interviewed for features in New Scientist, The Guardian, The BMJ and various TV programs have solicited his advice. The BBC filmed an experiment performed in his laboratory for broadcast in 'The History of Transplantation', first shown on BBC FOUR, Sept 3rd 2008. He has given many interviews for international science magazines including in Spain, France and Portugal, on US Public Radio, and Australian radio. With Prof. Paul French (Physics, Imperial College), he presented his research at the Royal Society Summer Exhibition in 2003. In 2000, he won the Oxford University Press Science Writing Prize.
Davis has given numerous public lectures in immunology, including four at The Royal Institution. In 2008, Baroness Susan Greenfield commented in a letter that Davis's Friday Evening Discourse was 'really one of the most enjoyable in years'. Davis has presented his research at the Edinburgh, Manchester and Cheltenham Science Festivals, at Science Show Off events, on the Guardian science podcast, at a TED youth conference for ~500 6th formers, York's Festival of Ideas and at Latitude music festival (where he will return in 2017). Davis enjoys a close relationship with the Hay Festival where he has presented his own work as well as chaired and helping arrange many other science speakers (8 events in 2016), including Steve Jones, Jeremey Farrar and Martin Rees. Davis has written a second popular-level book about the immune system which will be published by Penguin Random House late 2017/early 2018.
Year(s) Of Engagement Activity 2013,2014,2015,2016,2017
 
Description TV/Radio interviews 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I gave multiple TV and radio interviews regarding my book The Compatibility Gene, including on BBC Breakfast TV, NBC in the USA, and many radio stations in the UK, Europe, Australia, New Zealand, Canada and so on.

A huge number of people got to hear about immune system genes as a result of this activity - 1 million people watched the BBC Breakfast discussion alone.
Year(s) Of Engagement Activity 2012,2013,2014
URL http://www.davislab.ls.manchester.ac.uk/book/bookreviews/
 
Description Various media engagements 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I have interacted with many media outlets in relation to my research and been quoted widely as a spokesperson for discoveries in immunology. For example, I was quote on the front page of The Times newspaper on Feb 16th 2016 and featured in almost every UK paper (including The Telegraph, The Mirror and The Sun). I have also advised several TV programs.
Year(s) Of Engagement Activity 2012,2013,2014,2015,2016
URL http://www.telegraph.co.uk/news/science/science-news/12157788/Cancer-vaccine-that-remembers-disease-...