Revisiting Immunity: Challenging and Pioneering Immunological Research at #LINO23

Agora Talks are one of the hallmarks of the Lindau Nobel Laureate Meetings. They’re an excellent format for interactions between Laureates and Young Scientists, they’re a way to dive into more detail about research topics, and sometimes, they’re a place to share challenging ideas. This was exactly the case with Rolf Zinkernagel’s Agora Talk at #LINO23.

Remember, Remember

Zinkernagel is one of the pioneers of immunological memory. He shared the 1996 Nobel Prize in Physiology or Medicine for the discovery of how the immune system recognises virus-infected cells, and has dealt with several aspects of immunological memory. The Agora Talk started with a criticism of a recent trend in immunology. Immunology seems to sometimes drift away from the practical, medical field, Zinkernagel mentions, and becomes a purely academic, „art for the sake of art“ endeavor.

In particular, the Nobel Laureate addressed the question of immunological memory, the ability of the body to recognise pathogens encountered previously and respond to them efficiently. The adaptive immune system and antigen-specific receptor generation (TCR, antibodies) are responsible for this adaptive immune memory. But Zinkernagel argues that it’s the antigen that drives immune response in a repeated fashion.

The first question is why exactly this acquired immunological memory starts. Innate immune memory is well-documented in multiple organisms, both invertebrates and vertebrates. But acquired immunity is more confusing.

„If the first infection kills you, you don’t need memory. If you survive the infection, you also don’t need memory because you can survive it,“ the researcher notes. So, it’s not entirely clear what the exact evolutionary pressure driving this memory is

To follow up on this, Zinkernagel addressed the kinetics of antibody production. Here, he mentioned a specific problem: it matters how you measure antibody production. In many instances, the neutralising response (which is biologically relevant) drops below protection levels within about 30 to 60 days, the Laureate mentions. But if you measure antibody concentrations with the ELISA assay (Enzyme-Linked Immunosorbent Assay), this response seems to last far longer. So, the results are skewed by using ELISA, and often paint an incorrect picture, Zinkernagel claims. He adds that some researchers use this to get their papers published in various journals, but this falsely indicates long-lived memory cells. Ultimately, he says, if no antigen is present anywhere in the system, the immune response decays quickly. Therefore, he proposes that the idea of long-lived plasma cells that produce antibodies might be a myth.

The Laureate suggests that what is referred to as ‚memory‘ in the immune system may be linked to re-exposure to the antigen, either through natural infection or vaccination. He exemplified this with vaccines, and stressed that conventional vaccines are focused on antibody-based immunity rather than T-cell based immunity.

The idea that this immunological memory could be a myth is a challenging one, moderator Klas Kärre also emphasised – and one that would force us to rewrite quite a few textbooks.

But Zinkernagel isn’t the only one challenging established science. At the Next Gen, meeting, young researchers presented their own groundbreaking ideas.

Next Gen Science

Young Scientists are the heart and soul of the meeting – so it’s only normal that they too take the stage. At the City Theatre in Lindau, nine Young Scientists presented their work in immunology.

Dequina Nicholas, from the University of California Irvine, asked the audience to think of type two diabetes (T2D) in a different way. „Humans are not mice,“ Nicholas quipped, and in this simple realisation lies the key to many of our problems with diabetes. Many researchers use mice models to understand T2D, but T2D inflammation in mice is different from inflammation in humans. Nothing groundbreaking so far, but here, Nicholas strayed from accepted dogma.

According to her work, T2D chronic inflammation may have more to do with lipids rather than proteins. In essence, she says T2D can be viewed as an autoimmune response to lipids, and presented experiments that validate this view. This is particularly exciting because it opens up the door for potential treatments of T2D. Over 1 in 10 adults worldwide suffer from T2D, and the number is growing.

Mark Sorin, from McGill University, Canada, focused on the burden of lung cancer and how this burden can be reduced with tailored treatments. Lung cancer kills more people breast, prostate, and colon cancers combined. Our understanding and our ability to deal with lung cancer has improved, but there’s still much work to be done, Sorin says.

He explored the potential prognostic value of spatial features in the tumor microenvironment in lung cancer. He and his colleagues used data from a cohort of 400 lung cancer patients. They then used a method (that can use up to 40 markers at a time. By applying machine learning to this data, they found that some spatial features could predict which early-stage lung cancer patients are more likely to experience recurrence after surgery. This is useful in two ways. Firstly, it means that patients who are not likely to experience this can be spared the chemotherapy. Secondly, in patients who are likely to experience recurrence, physicians can focus on therapy more than on surgery. The Young Scientist mentioned that he and his colleagues are now working to reduce the number of markers and make it clinically available.

Meanwhile, YeEun Kim from Stanford University focuses on hematopoietic cells. These are immature cells that are found in peripheral blood and bone marrow and can differentiate into all types of blood cells. In particular, she looks at lymphoid progenitor cells (also known as lymphoblasts), precursors to other mature blood cell types. These lymphoid progenitors are difficult to study because they’re scarcely present in the bone marrow and they’re incompatible with humanised mouse models.

Kim has identified key protein markers that enable the detection and study of these lymphoid progenitors. Ultimately, this enables a fine mapping of the hematopoietic progenitor cells in the bone marrow. Additionally, she has found certain surface markers specific to the lymphoid progenitor cells. This allows them to be distinguished from other progenitor cells. These cells have shown the potential to be cultivated in vitro, where they can be used to create potent T cells and behave robustly.

More to Come

These were just some of the inspiring presentations at the Next Gen Science Session, and clearly, the future of immunology seems bright. The questions and discussions following the presentation also show that there’s a lot of potential for collaborations between researchers from different fields.

However, it’s clear that there are plenty of unresolved questions and unexplored areas in the field of immunology. This is a challenge from a clinical perspective, but it also serves as a reminder of the immense potential for the discoveries and progress that awaits.

The inspiration and information that Young Scientists draw from the Lindau Nobel Laureate Meeting can play a role in answering these unresolved questions. As new tools for imaging and analysing data are becoming more relevant, the boundaries of our understanding in immunology continue to expand.