Generation and Function of Antigen-specific Regulatory T cells

Lead Research Organisation: University of Birmingham
Department Name: Immunity and Infection

Abstract

The immune system is a powerful weapon, and the diseases that ensue when it attacks part of our own body (autoimmunity), rather than fighting infections, can be devastating. One example is diabetes in which the immune system attacks the pancreas. Recently, scientists have identified a new group of white blood cells (termed regulatory T cells) which have the specific task of preventing autoimmunity in normal individuals. We know that in mice, eliminating these cells is sufficient to trigger multiple autoimmune diseases. This raises the possibility that people develop autoimmune diseases because they somehow fail to produce enough regulatory T cells, or because the ones they do make cannot function properly. If indeed this is the case, we could potentially treat autoimmune diseases by injecting people with regulatory T cells, or with treatments to stimulate their production. My research exploits a novel mouse model which allows us to dissect how the generation and function of regulatory T cells is controlled. This information will potentially help us to design strategies to modulate regulatory T cells in individuals with autoimmunity with the aim of controlling their disease.

Technical Summary

The reason why the immune system attacks self tissues in certain individuals leading to autoimmune disease is still not known. This does not seem to simply reflect a failure to delete self-reactive T cells during thymic development, since T cells which recognize self-proteins are also present in healthy individuals. An increasingly likely alternative is that disease results from defects in the peripheral tolerance mechanisms that normally control self-reactive T cells in healthy individuals. A major aspect of peripheral tolerance is the role played by a specialized subset of lymphocytes termed regulatory T cells (Treg). As a consequence of the overwhelming evidence indicating the importance of this population, Treg are now a recognized component of cellular immunity. To explore the function of Treg in a defined way I have developed an experimental system for the production of Treg whose specificity is directed by a transgenic T cell receptor (TCR). Since these cells can be stimulated with a known antigen and tracked with a clonotypic antibody, they can be used to tackle questions that have previously not been possible to address. For the first time, the antigen-responsiveness of Treg can be addressed under physiological conditions, using the clonotypic antibody to track the transgenic Treg. Furthermore, I have also developed systems to study how these Treg inhibit inflammation induced by pathogenic CD4 cells specific for the same antigen. This system therefore represents a significant step forward from crude analysis of polyclonal CD25+ populations and instead allows analysis of a defined cohort of Treg as they respond to their specific antigen. The aim of this proposal is to use this novel transgenic model to advance our understanding of how Treg develop in response to endogenous antigens and to unravel the mechanisms by which they inhibit organ-specific autoimmunity.

Publications

10 25 50
 
Description Diabetes UK, PhD Studentship
Amount £70,500 (GBP)
Funding ID 08/0003762 
Organisation Diabetes UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2009 
End 10/2012
 
Description JDRF Project Grant
Amount $445,500 (USD)
Funding ID 1-2009-355 
Organisation Juvenile Diabetes Research Foundation (JDRF) 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2009 
End 06/2012
 
Description MRC Senior Non-Clinical Fellowship
Amount £2,200,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2009 
End 02/2016
 
Description Wellcome Trust Project Grant (How do B cells control T cell pancreas infiltration?)
Amount £304,000 (GBP)
Funding ID 085896 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2009 
End 02/2014
 
Description MRC Centre Collaboration 
Organisation University of Birmingham
Department MRC Centre for Immune Regulation
Country United Kingdom 
Sector Academic/University 
PI Contribution My research team has both contributed to and benefited from interactions with colleagues within the MRC Centre for Immune Regulation.
Collaborator Contribution Provision of PhD studentships and of research infrastructure support for my group.
Impact All of the publications produced by my group have been supported by the infrastructure of the MRC Centre for Immune Regulation. This reflects not just support for facilities (eg cell sorting) but also interaction and scientific discussion between colleagues within the Centre.
Start Year 2006
 
Description Collaborative visit to MedImmune 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact To foster a new collaborative link with researchers at MedImmune (Gaithesburg, MD, USA), I visited their headquarters and presented some of the findings from my Career Development Award in the form of a seminar.

Useful discussion.
Year(s) Of Engagement Activity 2008
 
Description Collaborative visit to Wyeth Research 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact To foster new collaborative links with researchers at Wyeth (Boston, MA, USA) I visited and presented some of the data generated during my Career Development Award.

Useful discussion.
Year(s) Of Engagement Activity 2008
 
Description Invited speaker at British Society for Rheumatology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Health professionals
Results and Impact Invited speaker at the British Society for Rheumatology annual congress in Liverpool. I presented data generated as part of my Career Development Award for discussion.

Useful discussion.
Year(s) Of Engagement Activity 2008
 
Description Invited speaker at EuroSciCon meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Health professionals
Results and Impact Invited speaker at Euroscicon meeting entitled "Analysing the Phenotype and Function of Regulatory T cells". I presented data generated during my Career Development Award for discussion.

Useful discussion.
Year(s) Of Engagement Activity 2008
 
Description Invited speaker at Hopital de la Pitie-Salpetriere 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Invited speaker as part of the Immunology programme at Hopital de la Pitie-Salpetriere, Paris France. I presented data generated as part of my Career Development Award for discussion.

Useful discussion.
Year(s) Of Engagement Activity 2008
 
Description Invited speaker at Imperial College London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact Invited speaker for John Humphrey Lecture series. I presented data generated during my Career Development Award for discussion.

Useful discussion.
Year(s) Of Engagement Activity 2008
 
Description Invited speaker at King's College London School of Medicine at Guy's Hospital 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact Invited speaker in the Immunobiology & Infectious Diseases Seminar Programme at King's College London School of Medicine at Guy's Hospital. I presented data generated during my Career Development Award for discussion.

Useful discussion.
Year(s) Of Engagement Activity 2008
 
Description Invited speaker at La Jolla Institute for Allergy and Immunology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Invited speaker at La Jolla Institute for Allergy and Immunology, CA, USA. I presented data generated as part of my Career Development Award for discussion.

Useful discussion.
Year(s) Of Engagement Activity 2008
 
Description Press Event for World Diabetes Day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact World Diabetes Day (14th November) is commemorated by the world-wide lighting of landmark buildings in blue (the colour of the international diabetes symbol). I organised for Birmingham University's historic clock tower, Old Joe, to be illuminated blue for the evening. The aim of the exercise was to raise awareness of diabetes, in order to encourage screening of at-risk individuals, and also to highlight the research performed by myself and my colleagues at Birmingham University. The event was advertised on the University website in addition to the websites of the Juvenille Diabetes Research Foundation (JDRF) and International Diabetes Federation (IDF). The MRC press office were also notified. A press-release was prepared containing lay summaries of the research performed as part of my MRC Career Development Award along with research performed by my colleagues. The event was attended by local press.

Useful engagement with the local community.
Year(s) Of Engagement Activity 2008