“These are the fundamental questions that really need to be answered”

Monika Wolkers PhD

Monika Wolkers PhD

Monika Wolkers is a group leader at the Department of Hematopoiesis as from October 2010. Before she came to Sanquin she worked for the Netherlands Cancer Institute, the Academic Medical Center, Amsterdam, and the La Jolla Institute for Allergy and Immunology in the USA. Her research is mainly aimed at T cells and antigen presenting cells.

Can you tell us something about your current research here at Sanquin?
My focus is on T cells. T cells are important for fighting infections, and to protect us from recurrent infections. My main interest right now is how these memory T cells that protect us from recurrent infection are programmed so that they can quickly respond to re-infections, but at the same time do not respond too strongly, or at the wrong time – which would result in tissue damage. Specifically, if you are thinking of lung infections; T cells are present in the lung and protect us from infections. These memory T cells have high mRNA levels but they do not produce any protein of effector molecules. To understand how high levels of messenger RNA are maintained to ensure that memory T cells can respond quickly but without inducing immunopathology is currently the main focus of my lab.

Can you tell us why T cells are important for your health?
T cells actually have two important functions during infections: Firstly, during a primary infection with pathogens, they help clearing the infection to prevent a chronic infection. Secondly, we need them to be protected from recurring infections. That section is a very important fact: people who lack T cells continuously undergo re-infections with pathogens. We study the functionality of these memory T cells to understand how T cell responses can be modulated by vaccines such that infections can be best resolved.

What happens when T cells do not work properly?
If T cells do not function well or people lack them due to a genetic defect, it is very difficult to resolve infections, and infections become more easily chronic. Secondly, people are not protected from re-infection, and get sick again from the same pathogens.
However, if T cells are too active and not trained properly, people develop autoimmunity; think of rheumatoid arthritis, think of lupus, think of MS. These are diseases where the immune system is over-active, and where T cells produce too many effector molecules, in situations where no pathogen is to be fought. In those cases it would be desirable to define how T cell responses can be shut down.

What are the most important lines of research/approaches that have developed in your field over the past 5 or 10 years?
In the past 5-10 years, we have gained insights in transcriptional regulation of the functionality of T cells. Genetic screens and new approaches of microarray analysis and the development of blocking gene expression helped us unravel how effector molecules are regulated on transcription level. So we now know how and when messenger RNA for the effector molecules is generated. And that is why I think that the next challenge we are facing is to understand when and how the protein is produced, from reading the messenger RNA.
Another important development in the T cell field is something what people thought to be impossible thirty years ago: using T cell therapy for treating melanoma metastases; a treatment that appears quite successful in a subset of patients. To make this treatment more effective and suitable for an even larger patient group is the next challenge.

Are there any other challenges in your research field?
We have made great improvements to elicit better immune response in order to increase the activity of T cells. But there are still gaps: how are memory T cells formed, and how are they maintained? How are T cells kept unresponsive while expressing mRNA for the effector molecules? What does a memory T cell need to get reactivated? These are the fundamental questions that really need to be answered in order to tackle issues that are encountered in the clinic – something that many people do not realize: fundamental research is pivotal to make the real improvements in the long run in medical sciences. There is definitely big movement forwards but I am absolutely convinced that without the fundamental research we have nothing to build upon.

Why does your line of research matter? Why should people put money into it?
Currently we lack the fundamental insights how RNA is regulated in T cells. We scarcely understand how mRNA levels are maintained in T cells and what the requirements are to control the production of effector molecules. It has become evident from the micro-array studies (that measure the mRNA levels in cells) of the past years that mRNA levels do not always represent the protein profile, but how the production of proteins is regulated is not yet understood.
I definitely think that this knowledge is crucial to generate the tools to modulate T cell responses, but our understanding in post-transcriptional regulation in this field is still in its infancy. The methods to assess this process are just being developed, and open the opportunity to study these RNA regulatory processes in situations where T cells are dysfunctional.

Who or what will benefit from your research?
In the coming 3-5 years, my research will primarily help to define the fundamental mechanisms that define how T cell responses are induced and maintained. In the long run, this knowledge will help us define how we can manipulate T cell responses, both to reactivate cells that have become tolerant, but also how to shut down overactive T cell responses.
Interestingly, the mechanisms we study are highly conserved. We find them in human and mouse T cells, and both in T helper cells that facilitate the generation of immunoglobulins, and in cytotoxic T cells. In addition, it also has become clear that the effector function in other cell types like NK cells and macrophages is regulated on the level of mRNA stability and translation.

How does your research suits Sanquin?
Firstly, I believe that it is critical that a blood research institute like Sanquin requires a strong arm of fundamental research to tackle the bottle necks we encounter during the development of blood products and of vaccines.
My research line is very basic, and will not immediately result in changes of the current protocols and reagent. It will rather form the basis of long-term investments to generate more optimal vaccines and therapies.


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