Structural Plasticity in Antigen Selection
Lead Research Organisation:
University of Southampton
Department Name: Centre for Biological Sciences
Abstract
Our bodies have evolved an intricate and powerful system to distinguish "self" from "non-self" called the immune system. This formidable task force allows us fight off foreign invaders such as viruses and bacterial pathogens. Since it can cause devastation and disease when it is going wrong, e.g. by attacking the self, such as in auto immune diseases, it needs to be highly regulated and finely tuned.
The proposed research investigates a key process to regulate to power of the immune system. Almost every cell in an individual constantly presents samples of short protein fragments from the inside of the cell to the immune system. If these samples are recognised as foreign, the cell will be destroyed. Hence, the control over which peptide samples are shown to the immune system constitutes a key control mechanism to direct the immune response. We are investigating the molecular mechanism of how these representative samples are selected at the cellular level and at the molecular level. We propose that the ability of the protein, called MHC, that recognises the peptides to be malleable and change shape is essential to perform the selection task. We hope that by understanding the molecular nature of this recognition process and its relationship to directing the immune response we will in the future develop new ways of fighting diseases such as cancer and auto-immune diseases by directing an individual's capacity to eradicate what it perceives as non-self.
The proposed research investigates a key process to regulate to power of the immune system. Almost every cell in an individual constantly presents samples of short protein fragments from the inside of the cell to the immune system. If these samples are recognised as foreign, the cell will be destroyed. Hence, the control over which peptide samples are shown to the immune system constitutes a key control mechanism to direct the immune response. We are investigating the molecular mechanism of how these representative samples are selected at the cellular level and at the molecular level. We propose that the ability of the protein, called MHC, that recognises the peptides to be malleable and change shape is essential to perform the selection task. We hope that by understanding the molecular nature of this recognition process and its relationship to directing the immune response we will in the future develop new ways of fighting diseases such as cancer and auto-immune diseases by directing an individual's capacity to eradicate what it perceives as non-self.
Technical Summary
Antigen processing describes the cellular mechanisms that lead to the selection of antigens inside a cell for the presentation to the immune system. This process forms a critical component in eliciting and directing an immune response. Hence, understanding the control of the process at the molecular level potentially offers new avenues of controlling infections, cancer and auto-immune diseases.
We are integrating cellular biochemistry and systems modelling with structural biology - NMR, molecular dynamics simulation and biophysical measurements - to determine the molecular mechanism of antigen processing.
Two key players, MHC class I and tapasin, have been identified as shaping the antigen repertoire. Furthermore, by analysing cellular experiments that monitor the time dependency of the shaping of the peptide repertoire by these players using systems modelling we could identify specific molecular reaction rates and protein states that control the biological outcome. The analysis implies that peptide selection by MHC class I depends critically on the presence of an intermediate conformational state of MHC and that tapasin enhances the rate of exchange between the intermediate and the fully formed MHC:peptide complex.
We are proposing a set of experiments to study the nature of the MHC intermediate and its interaction with tapasin using NMR in conjunction with molecular dynamics simulations and to use kinetic analysis to establish the reaction scheme and associated rates for the MHC peptide binding as well as the role of tapasin in this. We choose mouse derived MHC alleles for technical reasons and because the feasibility of follow-up studies on whole animal physiology using established mouse models for cancer and infection that would not be possible in humans.
We think that being able to link a significant biological function to a transient protein state has wider implications for our understanding of how proteins may govern biological processes.
We are integrating cellular biochemistry and systems modelling with structural biology - NMR, molecular dynamics simulation and biophysical measurements - to determine the molecular mechanism of antigen processing.
Two key players, MHC class I and tapasin, have been identified as shaping the antigen repertoire. Furthermore, by analysing cellular experiments that monitor the time dependency of the shaping of the peptide repertoire by these players using systems modelling we could identify specific molecular reaction rates and protein states that control the biological outcome. The analysis implies that peptide selection by MHC class I depends critically on the presence of an intermediate conformational state of MHC and that tapasin enhances the rate of exchange between the intermediate and the fully formed MHC:peptide complex.
We are proposing a set of experiments to study the nature of the MHC intermediate and its interaction with tapasin using NMR in conjunction with molecular dynamics simulations and to use kinetic analysis to establish the reaction scheme and associated rates for the MHC peptide binding as well as the role of tapasin in this. We choose mouse derived MHC alleles for technical reasons and because the feasibility of follow-up studies on whole animal physiology using established mouse models for cancer and infection that would not be possible in humans.
We think that being able to link a significant biological function to a transient protein state has wider implications for our understanding of how proteins may govern biological processes.
Planned Impact
Academic impact: The academic impact of the current project will be in a number of areas as the project combines cellular biochemistry, systems modelling with NMR, molecular dynamics simulations and biophysical measurements in addition to the broader scientific community whose research focuses on immunology and structural biology. In particular our proposed project will benefit the following academic communities:
1. Molecular Immunologists who will benefit from the results and the methodology of the proposed study.
2. Structural biologists with interests in protein structure and function relationships in particular in protein dynamics.
3. Biophysicists interested in the protein ligand binding and kinetics
4. The systems biologist community will benefit from the models we develop as they can be adapted to other pathways such as MHC class II. In addition systems biologists interested in understanding the molecular events associated with the trafficking of proteins between different intracellular compartments, will also benefit.
5. NMR community will benefit from the development and application of techniques for the analysis of protein dynamics as well as protein/protein interactions.
6. Molecular simulation and modelling community who will benefit from the applications and data generated in this project.
7. Academic researchers working on the molecular basis of viral infections, cancer or auto-immune diseases as novel mechanism in the control of these diseases are discovered.
8. Our association with two doctoral training centres (Complex Systems Simulations and Biology) will of course provide training of researchers in both fields.
Public engagement: Aspects of the current project will be used for outreach activities to local schools. The very visual element of molecular structures and simulations for the generation of 'movies' from simulation trajectories render them ideal for this purpose. In addition, to schools-based outreach, JW and TE will contribute to the award-winning science and engineering day hosted by the University of Southampton and is open to the general public.
We disseminate the aims, and results of our work in terms of biological complexity to the lay audience at various events including the science week the LifeLab project and arts exhibitions in collaboration with Tessa Coe. Lastly, we will create a page on the project website that is targeted towards the general public.
Commercial: We do not anticipate any immediate commercial impact to arise directly from our project. However, the systems and computational as well as biophysical techniques do have the potential for becoming a tool for rational drug-design. The methods developed here inform researchers at Microsoft in formulating languages and tools aimed at the general life science market.
1. Molecular Immunologists who will benefit from the results and the methodology of the proposed study.
2. Structural biologists with interests in protein structure and function relationships in particular in protein dynamics.
3. Biophysicists interested in the protein ligand binding and kinetics
4. The systems biologist community will benefit from the models we develop as they can be adapted to other pathways such as MHC class II. In addition systems biologists interested in understanding the molecular events associated with the trafficking of proteins between different intracellular compartments, will also benefit.
5. NMR community will benefit from the development and application of techniques for the analysis of protein dynamics as well as protein/protein interactions.
6. Molecular simulation and modelling community who will benefit from the applications and data generated in this project.
7. Academic researchers working on the molecular basis of viral infections, cancer or auto-immune diseases as novel mechanism in the control of these diseases are discovered.
8. Our association with two doctoral training centres (Complex Systems Simulations and Biology) will of course provide training of researchers in both fields.
Public engagement: Aspects of the current project will be used for outreach activities to local schools. The very visual element of molecular structures and simulations for the generation of 'movies' from simulation trajectories render them ideal for this purpose. In addition, to schools-based outreach, JW and TE will contribute to the award-winning science and engineering day hosted by the University of Southampton and is open to the general public.
We disseminate the aims, and results of our work in terms of biological complexity to the lay audience at various events including the science week the LifeLab project and arts exhibitions in collaboration with Tessa Coe. Lastly, we will create a page on the project website that is targeted towards the general public.
Commercial: We do not anticipate any immediate commercial impact to arise directly from our project. However, the systems and computational as well as biophysical techniques do have the potential for becoming a tool for rational drug-design. The methods developed here inform researchers at Microsoft in formulating languages and tools aimed at the general life science market.
People |
ORCID iD |
Joern Werner (Principal Investigator) | |
Tim Elliott (Co-Investigator) |
Publications
Elliott T
(2018)
Protein Plasticity and Peptide Editing in the MHC I Antigen Processing Pathway.
in Biochemistry
Illing P
(2021)
Kinetics of Abacavir-Induced Remodelling of the Major Histocompatibility Complex Class I Peptide Repertoire
in Frontiers in Immunology
Van Hateren A
(2015)
Plasticity of empty major histocompatibility complex class I molecules determines peptide-selector function.
in Molecular immunology
Bailey A
(2015)
Selector function of MHC I molecules is determined by protein plasticity.
in Scientific reports
Papakyriakou A
(2018)
The partial dissociation of MHC class I-bound peptides exposes their N terminus to trimming by endoplasmic reticulum aminopeptidase 1.
in The Journal of biological chemistry
Van Hateren A
(2017)
Direct evidence for conformational dynamics in major histocompatibility complex class I molecules.
in The Journal of biological chemistry
Description | We have charaterised the plasticity of peptide bound MHC allels and how this impacts the selection of potentially immunogenic agents. We have developped a novel systems appraoch for the description of cellualr processes that integrates both cellular and molecular data and hence allows the derivation of testsble predictions on both the cellular and molecular level. We have sucessfuly applied this modelling approach to the process of antigen selection and presentation. As a result we have developped a mathematical framework and a tool to explore wideranging sets of experimental data that will drive our understanding of antigen selection in healthy and disease states of cells and possibly organsims. For example this lets us explore how the antigen repertoire of a cell is changing when infected by a virus such as HIV. Another applciation of this framework is in the prediction of antigenic agents that are specific to specific cancers so that the immune system may be harnessed to elimiate these specific cells. |
Exploitation Route | The prediction of antigen repertoires on cell surfaces is pertinent ot immunotherapy approaches and vaccine design in a range of diseases. The platform we developped provides a framework to test mechanisic models of the process of antigen selection and presentation. The platform can be adapted and expanded to direct novel experiments as well as obtaining insight into the process and predict antigen complements. |
Sectors | Agriculture, Food and Drink,Chemicals,Digital/Communication/Information Technologies (including Software),Healthcare,Pharmaceuticals and Medical Biotechnology |
Description | BBSRC Industry |
Amount | £32,000 (GBP) |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 06/2005 |
End | 06/2006 |
Description | Marie Curie Action |
Amount | € 200,000 (EUR) |
Funding ID | 703530 |
Organisation | European Union |
Sector | Public |
Country | European Union (EU) |
Start | 09/2016 |
End | 09/2018 |
Description | WT funding NMR centre |
Amount | £77,000 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 04/2011 |
End | 04/2014 |
Description | Microsoft Research Cambridge |
Organisation | Microsoft Research |
Department | Microsoft Research Cambridge |
Country | United Kingdom |
Sector | Private |
PI Contribution | provided research project, expertise, data and network connections |
Collaborator Contribution | provided modelling expertise, informatics expertise, staff time and co-funding |
Impact | publications posters conference contributions mutli-disciplinary collaboration: immunology, structural biology, computer sciences |
Description | Art Exhibition |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Art exhibition with the purpose to communicate the nature of research and specifically structures of proteins |
Year(s) Of Engagement Activity | 2015 |
Description | Integrative Biology Conference |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Oral Presentation, participation in discussion Inform audience of research outcomes and ideas Outcomes: raised profile of resrach group and institution and UK science. invitattion to host similar event by organiser |
Year(s) Of Engagement Activity | 2016 |
Description | NIMR Mill Hill Talk 2012 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | discussion, networking not determined |
Year(s) Of Engagement Activity | 2012 |
Description | National Science Week 2012 |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | Yes |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | enthused participants not measurable by me |
Year(s) Of Engagement Activity | 2012 |
Description | National Science Week 2013 |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | enthused paraticipants not measurable by me |
Year(s) Of Engagement Activity | 2013 |
Description | National Science Week 2014 |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | enthused participants not measurable by me |
Year(s) Of Engagement Activity | 2014 |
Description | Opening of Soton Diffraction Centre |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | networking industrial research contract |
Year(s) Of Engagement Activity | 2011 |
Description | Workshop on Antigen Processing |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Undergraduate students |
Results and Impact | Workshop focused on research topic ca 40 UG and PGR students attended this workshop focused on mechansim of antigen processing influenced ideas and thinking on the topic of students increased intrest in undertaking research in this area |
Year(s) Of Engagement Activity | 2017 |