Paul Ehrlich and Ludwig Darmstaedter Prize 2023

Both the antibodies formed by B cells and structures on the surface of T cells have the ability to intercept antigens. They are collectively referred to as antigen receptors. Their enormous diversity is primarily due to a "lottery-like" combination of different gene fragments to form functional genes. This was first demonstrated almost 50 years ago using the example of antibodies. However, the details of this somatic recombination remained largely in the dark until Alt and Schatz shed more and more light on the matter. „The picture we have today of the diversification of antigen receptors in the immune system of vertebrates is primarily thanks to the two prizewinners“, explains the Chairman of the Foundation Board, Prof Dr Thomas Boehm. „They have taken our knowledge of the development of the immune system to a new level.“

Antigen receptors are proteins that consist of constant and variable components. In each antibody, for example, two heavy and two light chains are combined to form a ypsilon. The variable parts in the arms of the ypsilon determine which antigen the antibody can recognise. A different antibody matures in each B cell in our bone marrow. In total, our body can build around ten billion different antibodies, although it only has around 20,000 protein building blocks in the form of genes. It achieves this by using an extraordinarily daring procedure that makes cutting up and reassembling the DNA genetic information on certain chromosomes of maturing lymphocytes the norm.

The enzyme complex RAG1/2, discovered by Prof Dr David Schatz and colleagues, makes these cuts at predetermined locations. For the formation of the variable parts of heavy antibody chains, these sites are located on chromosome 14, where they flank relatively widely spaced sections in three different areas called V (for variable), D (for diversity) and J (for joining). From each of these regions, RAG1/2 cuts out a random section for each antibody. DNA repair enzymes then assemble a VDJ gene for the variable region of a heavy chain. Frederick Alt discovered the repair enzymes whose interaction leads to the linking of the excised sections. In the next step of B-cell maturation, the light chains are formed in a similar way, but in this case only a VJ recombination occurs.

However, the RAG enzymes do not wander aimlessly through the cell nucleus of immature lymphocytes. On the contrary, they bring the chromatin fibres, in which the DNA is wound up to save space, together again and again to form V(D)J recombination centres. There they perform chromatin scanning. A chromatin loop, which can be more than a million DNA letters long, runs through the recombination centre so that widely separated text sections can be securely linked together. The loop extrusion mechanism of V(D)J recombination described by Frederick Alt elegantly explains how these loops are created and pulled through the recombination centre.

Prof. Dr Frederick Alt has made further decisive contributions to the understanding of antigen receptor diversity. He was able to show that the combinatorial diversity is increased many times over by the enzymatic insertion of very short random DNA sequences, called N-nucleotides, at the interfaces of the gene segments to be linked. In B cells, antibody diversity is further potentiated by the phenomenon of somatic hypermutation. The normal rate of mutations affecting only one DNA letter is increased a million-fold in the regions of the V segments by an enzyme. Alt, Schatz and others showed how the enzyme carries out its work precisely. In doing so, they created a framework for solving the question of how B cells can make use of the enormous mutational capacity of AID for anti-maturation without running the risk of suffering tumour-inducing mutations.

Without the recombination-activating enzyme complex RAG1/2, the diversification of antigen receptors is impossible, the maturation of lymphocytes is impaired and a severe immunodeficiency is the result. It is therefore all the more remarkable that RAG1/2 was originally apparently a jumping gene - a transposon. Transposons are self-natural DNA parasites that have crept into our genome at some point and can move from one place to another. Due to their uncontrolled distribution, they can be involved in the development of diseases. According to the findings of David Schatz, RAG1/2 originates from a transposon that all jaw-bearing vertebrates, including us humans, tamed for their own purposes very early on in evolution. They had to fix it so that it could not jump any further. Schatz has shown which biochemical mechanisms they used for this purpose. He was also able to reconstruct the act of transposition over several stages in structural biology studies. In doing so, he has provided science with a fascinating look back at a revolutionary process at the beginning of vertebrate evolution: the development of the adaptive immune system in addition to the already existing innate immunity. Following on from this basic research perspective, translational research could open up new therapeutic perspectives for diseases in which our immune system plays a decisive role.

Notification "Paul-Ehrlich-Stiftung/Goethe-Universität Frankfurt" from 27 January 2023