CD4 T cell differentiation and regulation in autoimmune diabetes

Lead Research Organisation: University College London
Department Name: Immunology and Molecular Pathology

Abstract

Type 1 diabetes is an autoimmune disease in which cells of the immune system attack the pancreas and prevent it from producing insulin. Even if new insulin-producing cells are provided as a transplant, the immune system simply destroys these too. Medicines are available that suppress the entire immune system, but these have unwanted side effects. The key to successful treatment of type 1 diabetes is to pinpoint which cells cause disease so that these can be selectively targeted. We have performed a screen to characterise the immune cells that cause diabetes in a mouse model. This work has yielded a striking result; the cells are quite clearly a particular subset called follicular helper T cells. The possibility that this subset of immune cells could cause diabetes has not previously been explored. The proposed work seeks to investigate how these cells develop, and determine whether targeting this subset therapeutically can prevent or reverse diabetes. We will explore whether follicular helper T cells can be detected in blood samples from type 1 diabetes patients and will also take advantage of mouse diabetes models so we can test whether targeting these cells has beneficial effects.

Technical Summary

The importance of CD4 T cells in driving autoimmune diabetes has been recognised for some time. According to the original Th1/Th2 paradigm of CD4 T cell differentiation, diabetes was initially attributed to the Th1 subset. However, numerous subsequent observations appear at odds with this conclusion. Recent work has highlighted the potential for additional lineage choices for CD4 T cells, including the capacity to become Th17 cells, follicular helper T (TFH) cells or even Treg. Microarray data obtained using our TCR transgenic model of diabetes suggest the novel possibility that the T cells responsible for this autoimmune disease are TFH cells, the subset that specialises in providing B cell help. The proposed experiments will elucidate the molecular control of TFH cell differentiation and test the hypothesis that these cells play a causal role diabetes. The work will also explore our recent finding that IL-21, the signature cytokine for TFH cells, can counteract Treg suppression, potentially rendering this subset un-suppressible. Collectively our studies will provide new insight into the cellular and molecular pathways that influence CD4 cell differentiation and homeostasis in the context of an autoimmune response. Extending this work directly into human disease, this project will enumerate cells bearing TFH markers in patients with type 1 diabetes (T1D) and ascertain the value of such proteins as biomarkers of disease onset and progression. These studies have the potential to identify new therapeutic targets for the treatment of autoimmune diabetes. Taken together, this proposal constitutes an integrated programme of work that takes advantage of transgenic and gene-deficient mouse strains to generate refined hypotheses for testing in T1D patients. Ongoing iteration between murine and human work will enrich both areas of research and will maximise our progress in understanding the immunological abnormalities underlying autoimmune diabetes.

Publications

10 25 50

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Chamberlain JL (2011) B cell depletion in autoimmune diabetes: insights from murine models. in Expert opinion on therapeutic targets

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Kenefeck R (2015) Follicular helper T cell signature in type 1 diabetes. in The Journal of clinical investigation

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Ovcinnikovs V (2015) Regulatory T Cells in Autoimmune Diabetes: Mechanisms of Action and Translational Potential. in Progress in molecular biology and translational science

 
Description Horizon 2020 Innovative Training Network
Amount € 3,354,685 (EUR)
Funding ID Grant Agreement Number 675395 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 10/2015 
End 08/2019
 
Description MRC Programme Grant
Amount £1,676,980 (GBP)
Funding ID MR/N001435/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2016 
End 03/2021
 
Description Project Grant, DUK
Amount £207,509 (GBP)
Funding ID 12/0004477 
Organisation Diabetes UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2012 
End 08/2015
 
Description Project grant, BBSRC
Amount £648,863 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 07/2010 
End 10/2014
 
Description Project grant, DRWF
Amount £20,000 (GBP)
Organisation The Diabetes Research & Wellness Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2016 
End 03/2017
 
Description Project grant, Diabetes UK
Amount £279,643 (GBP)
Funding ID BDA: 15/0005253 
Organisation Diabetes UK 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2015 
End 03/2018
 
Description Project grant, MedImmune Inc
Amount £137,169 (GBP)
Organisation MedImmune 
Sector Private
Country United States
Start 02/2016 
End 01/2017
 
Description Project grant, Rosetrees Trust
Amount £58,440 (GBP)
Organisation Rosetrees Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2016 
End 01/2019
 
Description Project grant, Wellcome Trust
Amount £263,376 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2011 
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 MRC Centre for Medical Molecular Virology 
Organisation University College London
Department MRC Centre for Medical Molecular Virology
Country United Kingdom 
Sector Academic/University 
PI Contribution I am a member of the MRC Centre for Medical Molecular Virology at UCL.
Collaborator Contribution This is a collaborative partnership with regular meetings and a PhD studentship programme.
Impact N/A.
Start Year 2013
 
Description Diabetes Public Engagement Event, Wrexham 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact One of the post-doctoral researchers in my lab gave a presentation to families of children with type 1 diabetes.

Great interest and enthusiasm was shown for our research efforts.
Year(s) Of Engagement Activity 2010
 
Description Institute of Immunity & Transplantation Open Day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact I gave a presentation on my group's work at the Institute of Immunity & Transplantation Open Day 2015. This event was attended by scientists from throughout the UK as well as industry representatives and members of funding bodies.
Year(s) Of Engagement Activity 2015
 
Description Institute opening event 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The new Institute for Immunity & Transplantation (opened June 2013) held an opening event for the public, patient groups and other stakeholders. Presentations were given to describe the mission and research goals of the Institute.

The event increased local interest in medical research.
Year(s) Of Engagement Activity 2013
 
Description JDRF Diabetes Discovery Day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Dr Rupert Kenefeck, a postdoc in my group, gave a lay presentation about our Type 1 Diabetes research at the JDRF Discovery Day, 9th November, Hertfordshire.

Presentation was well received and resulted in considerable discussion.
Year(s) Of Engagement Activity 2013
 
Description JDRF Discovery Day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact I gave a presentation to a group of diabetic children and their parents at Think Tank Millennium Point in Birmingham. I talked about how my lab is trying to understand what causes type 1 diabetes (using MRC funding as well as funds from JDRF).

Further requests were made to engage with other parent groups.
Year(s) Of Engagement Activity 2010
 
Description JDRF Parliamentary event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact I attended a JDRF Parliamentary even, hosted by Jamie Reed MP to raise awareness of Type 1 Diabetes. The event included ~100 children and adults affected by type 1 diabetes along with politicians, researchers, healthcare professionals and research funders who came together to celebrate the UK's world-leading role in the fight against the condition.
Year(s) Of Engagement Activity 2016
 
Description Lab member speaking at Bromley Diabetes Group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The visit was an opportunity for my postdoc to explain our current research into the immunology of Type 1 Diabetes to Bromley Support group, who raise money for diabetes research. The event was enjoyable for everyone and sparked lots of discussion.
Year(s) Of Engagement Activity 2016
 
Description Medicine for Members Talk, Royal Free Hospital 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Approximately 80 members of the public attended an evening talk which was part of the Royal Free Hospital "Medicine for Members" series. These are informal evenings focusing on a particular area of medicine and are open to the public as well as hospital staff. Research performed in the Walker lab was discussed. The talk can be found on youtube at the URL below and has been viewed over 100 times.

The talk raised a great deal of interest and there was an extended session for questions and discussion afterwards.
Year(s) Of Engagement Activity 2014
URL https://www.youtube.com/watch?v=5utFdrjTJtI
 
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
 
Description Public Engagement Event for World Diabetes Day 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Press event for world diabetes day. The royal free hospital participated in the Blue Monument Challenge organised by the International Diabetes Federation. Purpose: raise awareness of diabetes.

Members of the public became aware that diabetes research was being performed at the royal free hospital.
Year(s) Of Engagement Activity 2013
 
Description School Assembly Talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Schools
Results and Impact Although it was a sombre event, I received very positive feedback regarding our research efforts.

I was told that people felt very positive about the presentation and it had increased their awareness of the importance of medical research.
Year(s) Of Engagement Activity 2011
 
Description Speaker at Diabetes UK London Volunteering Event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Supporters
Results and Impact The talk sparked lots of interest from Diabetes UK supporters and was followed by extensive informal discussions.

Several people said they had a much better idea of what research involved after my talk.
Year(s) Of Engagement Activity 2015
 
Description Speaker at ULLA Summer School 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact A group of international PhD students attended the ULLA Diabetes Summer School at UCL to hear about different aspects of diabetes research.

Lots of enthusiasm and interest. A request for a lab placement to learn more about our work.
Year(s) Of Engagement Activity 2013
 
Description Visit to Sandwell Diabetes Support Group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact The research talk was well received and generated a lively discussion.

N/A.
Year(s) Of Engagement Activity 2012
 
Description Visit to Sutton Voluntary Group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact I presented the research goals of my laboratory to Sutton Voluntary Group. This group comprises individuals who have a personal interest in diabetes and raise funds for research in this area.

The group was enthused by our research efforts and requested a return visit for an update next year.
Year(s) Of Engagement Activity 2010,2011