The BD Biosciences – EFIS partnership and the future of immunology – Interview with Prof. Rene A.W. van Lier, Sanquin Blood Supply Foundation, Amsterdam.

BD Biosciences recently signed an agreement with the European Federation of Immunological Societies (EFIS), with the aim of reaching out to the European immunology community. We are pleased to present an interview with Prof. Rene A.W. van Lier from the Sanquin Blood Supply Foundation, Amsterdam, and the past president of EFIS. Prof. van Lier spoke to us about EFIS, its goals and expectations, his research on tissue-resident memory T cells and his views on the future of immunology.

  1. To start, I would like to ask you about EFS, the organization and what it aims to do?

EFIS stands for the European Federation of Immunological Societies. We are an umbrella organization that unites all European national immunological societies, of which there are 35 now. There are about 14000 immunologists in Europe and the main aim of EFIS is to strengthen the European immunology community. We have a couple of instruments to do this. One of the most prominent ones is the European Congress of Immunology (ECI), which we organize every three years. This is jointly organised by the major European immunological societies among the 35. One thing we agreed upon is that in the year the ECI is organised, we will not be conducting any of our national meetings. This is to encourage people to go to the ECI and participate at the European level. The last ECI was held in 2018 in Amsterdam, and the next one will take place in Belgrade in 2021. Our other main instrument is our support of young people. We offer young immunologists short-term fellowships so they can go abroad for periods of up to three months to collaborate with others and bring back techniques to their home labs. This is a very good instrument as it connects people from different countries.

We also have allocations for bursaries that enable people to go to meetings. These scholarships are available only to young scientists (Ph.D. students and post-docs) and not to older, experienced ones.

A big chunk of work that we do goes into organizing smaller meetings. EFIS subsidizes several of them, like the school of immunology in Sardinia, and the Tatra meeting in Slovakia and many more. We also have smaller, more recent activities like the EFIS On Tour. The first one was in Budapest in 2016. The EFIS board meets every 3 to 4 months and we thought that it would be a good idea to meet the people from the national societies, who are doing all the work, and have a scientific symposium. This has proven to be very successful. We also have study groups, an initiative by Andreas Radbruch, the current President of EFIS, where people working on different disciplines come together.

It is important to note that nobody pays any dues to EFIS. To support our initiatives, we are closely involved with two journals – The European Journal of Immunology and Immunology Letters. The content review and the editing of the articles are done by EFIS people and we get compensated for that. This gives us funding for some of our activities. At some point, we thought we should expand and also involve corporate entities that would be willing to support some of our initiatives. The first one we are working with is BD, which has kindly agreed to sponsor our EFIS On Tour events. The first of these events supported by BD was held in Istanbul, on the 27th of September. The official signing was done by the BD Turkish representative, Isil Cevik, and we can now officially announce it on our website.

 

  1. So this is the first time you are partnering with a major manufacturer like BD. You did mention about support for your activities but what other expectation do you have from a company like BD, towards backing this kind of initiative?

In the end, it comes down to the fact that we are working with the same community. Our goals may be different. Of course, you are a company and you’ve got to earn money. But at the same time, you want to advance your techniques and your science. We as a community of European Immunologists are a database and knowledge base for you. You can do things we cannot do. For instance, our lab had made many antibodies and one of them was against a transcription factor. BD got interested and put a very nice label on it in a quality-controlled way that we could have never done, even though it is not a big commercial success yet. We have also worked together to create all kinds of flow cytometry panels. When I was trained, I used a single channel flow cytometer but now there are ones with several channels available. Our standard 20-panel FACS is now operational and we could not have done it without collaborating with BD. So that is our expectation. We are the same community but look at things from different angles.

 

  1. Now at BD, we are going beyond flow cytometry. We have a Multi-Omics portfolio for single-cell RNA sequencing. What are your views, as these techniques can complement flow cytometry in the kind of information they give?

At the beginning of summer, I was in Kos where I met from BD who told me that they were now conjugating oligos to antibodies (The BD™ AbSeq). I asked him to come to our EFIS On Tour as this is the progress we would like to make. We are now looking at the single-cell, label-free, and combining it with the labelling approach in flow cytometry and other techniques like MALDI, this is really the future. I like single cells and we do single-cell work too. But we also do proteomics, and flow cytometry is a kind of biased proteomics. We noticed that when we compare bulk RNA sequencing and bulk proteomics, we see big differences between the expression levels of proteins and mRNA. We know this from our biology books but we never realize it. We frequently think that if there is an expression of a gene there will be protein but that is not always the case. So it is important to look at things at the single-cell levels and take protein approaches on lower and lower cell numbers. That is a big challenge and I really like the approach with the oligo-conjugated antibodies.

 

  1. Can you tell us something about your research?

I am an MD by training and I focus on human immunology. I started in 1984, making many monoclonal antibodies against human T cells and began working on CD27, one of my pet molecules. We studied the biology of CD27 and used it to separate functionally distinct subsets of human T cells and NK cells. One of our key papers in this was in 19971 where we showed that in normal humans, it was possible to separate memory and resting effector type T cells using markers like CD8, CD27 and CD45RA.  This work continued, first with the bulk analysis and then with tetramer-MHC staining, flow, and other techniques. Then we started to work in clinical conditions, with subsets from organ transplant and cancer patients. From the blood, we then went to the organs. We started work on tissues, especially in the lungs; we had the first paper out in 20052 where we called them ‘T cells in the lung’, and –sadly in retrospect- we didn’t put a catchy label on them. In parallel, we started to work on CD27 in mice. In collaboration with Jannie Borst, then at the Netherlands Cancer Institute (NKI), we generated transgenic and knockout mice on the specific role of CD27, which is a co-stimulatory molecule, and on the differentiation of mostly CD8 cells into memory and effector T cells. In the human line, at some point, we started working on clinical samples. At that time, I was working at the Academic Medical Centre (AMC) in Amsterdam and was lucky to have a very good collaboration with a transplant immunologist, Ineke ten Berge. She sampled people after kidney transplants, who had developed primary cytomegalovirus (CMV) infection. We collected antigen-specific cells at different periods after primary infection and did transcriptomic analysis on them. We pulled out many genes, of which one was particularly interesting. It is a homolog of a transcription factor Blimp -1, which is widely studied in the immune system and is called Hobit. What makes Hobit interesting is that it is a transcription factor in human antigen-specific cells with cytolytic effector functions,  and we started studying this in mice. Then luckily, serendipity occurred. The thing is, that Hobit turns out to be the key transcription factor for tissue-resident memory T cells. So the two lines were working on could merge; one line was the lung cells we had and the other is the mouse model which showed that Hobit is needed to get the cells into the tissues. That’s now the main focus of the lab. We think that the barrier sites of these cells in the tissues – the skin, lungs, gut etc, play a key role in the first protection against incoming antigens. The cells just lie there in the epithelial layer and provide immediate protection when a bug enters. In mice we are working on the functions of this transcription factor and trying to address when a cell becomes a tissue-resident memory T cell, or when does it stop being a circulating memory T cell. In the human system, we have moved from normal immune responses to those against cancer. We find a lot of these tissue-resident memory T cells in tumors, in fact. So, if we could find out what they are doing there and how they can be used for therapy, it would be very useful.

 

  1. What is the future like? What are the burning questions in immunology and where do you see the research going?

There are a couple of real burning questions. I have been in immunology since 1984. Then as now, immunology is important because of diagnostics, auto-immune diseases and the understanding of transplant immunology. If you now look at the therapeutic interventions, immunology is still promising but it must deliver at some point. With the biology that we know and the conceptual issue of checkpoint regulations of lymphocytes and leukocytes, immunology is really entering into the clinic. We are translating what we know into action. I was the chair of the Dutch Society of Immunology and in Holland, research funding often comes from charities. Some of these charities are disease-oriented, like we have the kidney foundation, the heart foundation and the rheumatology foundation. What we could put across to these foundations, other than the different symptoms and patients, is that the basic de-regulation of the immune system may be similar in patients with different diseases. Now we have proposed to them the importance of working together to find common mechanisms, which could impact all these diseases. This has started about a year and a half ago with the support of the government, and we have trans-sectional immunology programs. This is the way immunology should go, by looking at big issues that may be important. Checkpoint regulation is, of course, a big issue, but I think that also immune-metabolism will explode in the coming years. People are starting to see that the differentiation of immune cells is not just dependent on the transcripts and proteins but also on the metabolic status of the immune cells. Couple that to the ideas on general immuno-pathophysiology and there will be a big integration of these ideas. At some point, this may go beyond our comprehension, and so we are starting to see that immunologists are increasingly tying up with bioinformaticians and thereby include artificial intelligence technologies to process and understand data. Again, I started as an MD and we should also try to do this in a way that patients and society can benefit. Some of these things, like personalized adoptive T cell therapies, should in my opinion, be run by not-for-profit institutes which can also provide sustainable patient care as the costs for these are enormous. So, we must try to make them available to people.

 

1.Hamann D, Baars PA, Rep MH, Hooibrink B, Kerkhof-Garde SR, Klein MR, van Lier RA. Phenotypic and functional separation of memory and effector human CD8+ T cells. J Exp Med 1997; 186:1407-18.
2. de Bree GJ, van Leeuwen EM, Out TA, Jansen HM, Jonkers RE, van Lier RA. Selective accumulation of differentiated CD8+ T cells specific for respiratory viruses in the human lung. J Exp Med 2005; 202:1433-42.

 

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