The supramolecular dynamics of human immune cell recognition and communication
Lead Research Organisation:
Imperial College London
Department Name: Dept of Medicine
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.
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.
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.
