Thymic involution: how a chance observation saved years of work

An interview with the VIB following the recent publication of our article:

The thymus is an organ crucial for the functioning of our immune system. During aging or infection the thymus can shrink severely, a process called involution. Although the mediators that trigger involution are known, the mechanisms regulating the sensitivity to their presence remained a mystery. Now, Smaragda Papadopoulou from the Bart De Strooper Lab and James Dooley from the Adrian Liston Lab describe in Nature Immunology a microRNA network that plays a key role. A chance observation kick-started the collaboration.

What did you discover about the regulation of thymic involution?

Adrian Liston: The main finding was the tight regulation by miR-29a over sensitivity to thymic involution. miR-29a serves to suppress the involution response, in effect "saving" involution for those situations where we really need it, such as during a major infection. Knowing what drives the reaction of the thymus is important, since it is the only place where T cells can develop. No thymus, no T cells, no infection prevention.

Is there an application side to those results?

For most of us, being born with a healthy thymus, we will generate enough T cells to last a life-time. Thymus involution during an infection is generally not a problem, nor the slow progressive involution that occurs from birth. The major problem is among the very elderly and with radiation/chemotherapy patients. If we could reverse thymic involution in those populations, we could rejuvenate their T cell population, providing them with a younger, more robust, immune system.

How did you go from studying regulatory T-cells to the regulation of thymic involution?

We have been interested in both the thymic epithelium and microRNA for years, so it was natural for us to look at what microRNA does in the thymic epithelium. As for thymic involution in particular, that was observation-driven. When we knocked out microRNA in the thymic epithelium using a Cre-Lox system, the main phenotype was chronic involution. But working out which microRNA is important was an enormous task. The big breakthrough for us was serendipitous. The Bart De Strooper Lab had generated a novel knockout mouse with a defect in one particular microRNA, miR-29a, to look at the neurophenotype. A conversation, a quick look and just by chance this microRNA turned out to be the one we needed for our lead. This enabled us to start a cross-disciplinary collaboration years before anyone else even knew there was a story there.

Did you use or design any new technologies for this research?

Far from it. The most important read-out in this work was the humble cell count. There are still enormous opportunities for high-level research using basic technologies. In this particular case the edge we had was a new mouse strain (the miR-29a knockout) and a new permutation of old mouse strains (Foxn1-Cre and Dicer-flox), but the rest was simply applying old techniques to a new problem. Immunology has so many fascinating questions that remain under-investigated that we spend our time working out which ones to tackle next, rather than designing new technology.

What’s the next step in your microRNA research?

MicroRNA are such interesting molecules. So tiny, they hold only a fraction of the information of a normal gene, yet they are incredibly versatile, affecting multiple completely unrelated targets in every cell type. We pretty much cracked the role of miR-29a in the thymic epithelium, but we are sure it is doing a lot more in other cell types of the immune system.

For the full research results see:

Aikaterini S. Papadopoulou#, James Dooley#*, Michelle A. Linterman, Wim Pierson, Olga Ucar, Bruno Kyewski, Saulius Zuklys, Georg A. Hollander, Patrick Matthys, Daniel H. Gray, Bart De Strooper and Adrian Liston. #Equal first authors. *Co-corresponding authors. 'The thymic epithelial microRNA network elevates the threshold for infection-associated thymic involution via miR-29a mediated suppression of the IFN-α receptor.' 2012. Nature Immunology. 13 p181.  Pubmed | Direct access

Autoimmune Genetics Laboratory in the news

In De Staandard, 26th July

KUL en VIB boeken doorbraak in strijd tegen immuunziekten

De K.U.Leuven en het VIB (Vlaams Instituut voor Biotechnologie) hebben een stap voorwaarts gezet in de strijd tegen immuunziekten.

De onderzoekers ontdekten een nieuw type cellen dat kan helpen om het evenwicht te bewaren tussen een overactief en een onvoldoende actief immuunsysteem. Dat laten beide instellingen dinsdag weten in een mededeling.

Talloze mensen lijden aan een ziekte van het afweer- of het immuunsysteem. Als het systeem overactief is, kan dat leiden tot allergieën en auto-immuunziekten zoals Systemische lupus erythematosus (afgekort SLE), een aandoening waarbij het afweersysteem zich op overdreven wijze tegen het eigen lichaam richt. Maar is het afweersysteem onvoldoende actief, dan treden infecties of tumoren op. Het juiste evenwicht vinden, is dus essentieel.

Adrian Liston, van het VIB en de K.U.Leuven, is een nieuw type cellen op het spoor die helpen om dat evenwicht te bewaren. De ’folliculaire regulatorische T-cellen’ (Tfrs) zetten een rem op de groei van afweercellen die antistoffen aanmaken. Verder onderzoek zal het uiteindelijke belang van de Tfr-cellen moeten uitwijzen.

In Het Nieuwsblad, 26th July

KUL en VIB boeken doorbraak in strijd tegen immuunziekten

De K.U.Leuven en het VIB (Vlaams Instituut voor Biotechnologie) hebben een stap voorwaarts gezet in de strijd tegen immuunziekten.

De onderzoekers ontdekten een nieuw type cellen dat kan helpen om het evenwicht te bewaren tussen een overactief en een onvoldoende actief immuunsysteem. Dat laten beide instellingen dinsdag weten in een mededeling.

Talloze mensen lijden aan een ziekte van het afweer- of het immuunsysteem. Als het systeem overactief is, kan dat leiden tot allergieën en auto-immuunziekten zoals Systemische lupus erythematosus (afgekort SLE), een aandoening waarbij het afweersysteem zich op overdreven wijze tegen het eigen lichaam richt. Maar is het afweersysteem onvoldoende actief, dan treden infecties of tumoren op. Het juiste evenwicht vinden, is dus essentieel.

Adrian Liston, van het VIB en de K.U.Leuven, is een nieuw type cellen op het spoor die helpen om dat evenwicht te bewaren. De ’folliculaire regulatorische T-cellen’ (Tfrs) zetten een rem op de groei van afweercellen die antistoffen aanmaken. Verder onderzoek zal het uiteindelijke belang van de Tfr-cellen moeten uitwijzen.

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.