Balance of the immune system determined by newly discovered T cells

From the VIB Press release: A newly discovered cell type helps to determine the balance of the immune system. The cells are derived from FoxP3(+) regulatory T cells, which recently have been demonstrated to suppress disease during transplantation. Nature Medicine and Blood, two high-ranking scientific journals, are publishing findings by the Autoimmune Genetics Laboratory about this discovery.

 

Innumerable people suffer from immune system disorders. If the immune system is overactive, it can result in allergies and autoimmune diseases such as Systemic lupus erythematosus (SLE). If the immune system is not active enough, infections or tumors occur. It is therefore essential to maintain the right balance.

 

The Autoimmune Genetics Laboratory is investigating a new type of cell that helps to maintain this balance. These ‘follicular regulatory T cells’ (Tfrs) suppress the process by which antibodies are produced during infections and SLE. The Tfrs themselves are daughter cells of FoxP3(+) T cells, key regulators of the immune system.

 

From lupus to cancer

In order to prevent disease the immune system needs to be in balance. If the system is too active, it produces antibodies against harmless substances, as is the case with allergies. An overactive immune system can even attack the body’s own tissues, causing autoimmune diseases such as lupus, rheumatism and diabetes. However, an insufficiently active immune system opens the way for rampant infections and tumors.

 

A complex network of regulatory cells is active to maintain this balance in our bodies. This must ensure that the immune system is sufficiently active and selective so that pathogenic intruders are recognized and eliminated in good time, but at the same time that it does not get out of control. This network of regulatory and activating cells is a long way from being fully unraveled. Dozens of researchers around the world are working to map this network.

 

This Tfr research is a joint collaboration between researchers from VIB-K.U.Leuven, the Australian National University (Aus) and the University of Cambridge (U.K.).

 

Publications

Linterman et al, Foxp3(+) follicular regulatory T cells control the germinal center response, Nat Med, 2011, doi:10.1038/nm.2425

 

Tian et al, Foxp3+ regulatory T cells exert asymmetric control over murine helper responses by inducing Th2 cell apoptosis, Blood, 2011, doi:10.1182/blood-2011-04-346056

FWO post-doctoral fellowship awarded to Bénédicte Cauwe

This week it was announced that Dr Bénédicte Cauwe won an FWO post-doctoral fellowship to perform research in the Autoimmune Genetics Laboratory. Dr Cauwe recently finished her PhD in the laboratory of Professor Ghislain Opdenakker at the Rega Institute and will continue her research on systemic lupus erythematosus at the Autoimmune Genetics Laboratory.

IRO fellowship won by Dina Danso-Abeam

Today it was announced that Ms Dina Danso-Abeam in the Autoimmune Genetics Laboratory was awarded an IRO fellowship to perform research towards her PhD. 

The Autoimmune Genetics Laboratory in 2010

All the members of the Autoimmune Genetics Laboratory, at our end of year dinner.

Juvenile Diabetes Research Foundation

Good news in funding appears to come in pairs. The Juvenile Diabetes Research Foundation is supporting the Autoimmune Genetics Laboratory through a Career Development Award. This is a grant that I am particularly happy to receive, not just for the science that will come out of it, but because I have been a long-time admirer of the JDRF, who tirelessly raise money for research on type 1 diabetes. They are not only the leading sponsor of type 1 diabetes research (spending over $1.4 billion on research since 1970), but also take an active role in coordinating researchers and integrating patient into trials to ensure that the best results come from the money spent. As a PhD student with Chris Goodnow, I always joined in the Walk for the Cure fundraiser, and JDRF sponsored my conference travel to the International Immunology Congress in 2004.

Now the JDRF is supporting our research project on the contribution of non-hematopoietic defects to autoimmune diabetes:

The Non-obese diabetic (NOD) mouse is one of the best studied models of common autoimmune disease in humans, with the spontaneous development of autoimmune diabetes. Similar to the way multiple autoimmune diseases run in families of diabetic patients, the NOD mouse strain is also susceptible to multiple autoimmune diseases, with specific disease development depending on slight alterations in the environment and genetics. These results demonstrate the complexity of autoimmune genetics – in both human families and inbred mouse strains there appear to be a subset of genetic loci that skew the immune system towards dysfunction and an additional subset of genetic loci that result in this immune damage affecting a particular target organ. In the case of NOD mice and type 1 diabetic patients these additional genetic factors result in damage to the beta islets of the pancreas. While the previous emphasis on type 1 diabetes was strictly on the immune system, this model suggests the important role the pancreas may play in the disease process. If certain individuals harbour genetic loci that increase the vulnerability of pancreatic islets to immune-mediated damage, the combination of immune and pancreatic loci could provoke a pathology not caused by either set of genes alone.

Current approaches to genetic mapping in both mice and humans are confounded by the large number of small gene associations and are not able to discriminate between these functional subsets of genetic loci. However, we have developed an alternative strategy for functional genetic mapping. Instead of mapping diabetes as the sole end-point, with small genetic contributions by multiple genes, we map discrete functional processes of diabetes development. This has three key advantages. Firstly, as simpler sub-traits there are fewer genes contributing, each with larger effects, making mapping to particular genes more feasible. Secondly, by mapping a functional process within diabetes we start out with functional information for every gene association we find. Thirdly, by mapping a series of functional processes and then building up this genetic information into diabetes as an overall result we gain a more comprehensive view of diabetes, as a network of genetic and environmental influences that cause disease by influencing multiple systems and processes.

In this project we propose to use the functional genetic mapping approach to probe the role of the pancreatic beta islets in the development of diabetes in the NOD mice. We have developed a transgenic model of islet-specific cellular stress which demonstrates that NOD mice have a genetic predisposition of increased vulnerability of the pancreatic islets to dying and hence the development of diabetes. This is a unique model to analyse the genetic, cellular and biochemical pathways that can be altered in the pancreas of diabetes-susceptible individuals, shedding light on the role the beta islets play in the development of disease.

European Research Council funding

A major investment of my time last year and this year was in putting together an application for a European Research Council Start grant. The process was quite an ordeal, with both a substantial written grant and a challenging oral defense, probably consuming over 100 hours of my time. Fortunately, with excellent independent researchers in the laboratory, great research continued to be done in the laboratory while I was locked away with the computer.

Being open to researchers across Europe, in any discipline, the competition is fierce, however there are some large advantages to the ERC Start grant process: 1) the committee looks favourably upon large ideas, rather than safe ideas; 2) the competition is segregated according to career stage, so that I was only competing with other researchers less than five years out from their PhD; 3) the funding is sufficient in scale and duration to really put forward a grand plan. Just recently I found out that the application was approved, and the VIB put out the following press release:

VIB receives high score from European Research Council (ERC)
Two young top researchers awarded €1.5 million research grants!

Leuven - VIB landed two research grants worth 1.5 million euros each. The prestigious grants are courtesy of the European Research Council (ERC) and are aimed at giving talented young scientists the opportunity to develop their own research team. The honor fell to Adrian Liston and Patrik Verstreken, both recently transferred to VIB-K.U.Leuven from abroad.

The European Research Council
ERC was created to encourage excellent research in Europe. ERC starting grants give young talented researchers the opportunity to develop a research group. At present, there are still too few opportunities in Europe for young scientists to initiate and lead their own research, which is extremely unfortunate as it results in top researchers leaving the region to develop their careers elsewhere.

Adrian Liston studies autoimmune diseases.
The immune system is our body's defense system and allows it to fight off foreign substances and micro-organisms. In people with an autoimmune disease, the immune system has gone awry: it can no longer distinguish between the body's own and foreign substances and ends up attacking vital tissues and organs. Adrian Liston studies immune system cells (T cells) that are responsible for this malfunction. With his ERC research grant, he plans to bridge the gap between his research on mice models and humans. This may be a first step in the development of new therapies for autoimmune diseases.

Patrik Verstreken explores the communication between brain cells.
Brain disorders take a major toll on society. Many brain diseases are caused by the disruption of communication between brain cells. Finding a solution depends on understanding this communication in the smallest detail. Patrik Verstreken uses the fruit fly as his model organism for studying genes involved in the communication between brain cells. The ERC research grant gives him the opportunity to expand his research to more complex neural communication networks that control behavior. This step is crucial if we are to understand neurological disorders such as Parkinson's disease.