Obituary: Dr Zoltan A. Nagy (1941–2020)

We could say that sudden death of Dr Zoltan A. Nagy from COVID-19 on 8 December 2020 (in his 80th year) marks the end of an epoch in immunology. Just a few weeks before he could have gotten a vaccine, and perhaps enjoyed the benefit of the research in which he invested his working zeal and effort, SARS-Cov-2 claimed another victim - an immunologist. Although retired, Zoltan gladly joined in sharing his knowledge with a group of immunologists interested in the conceptual and fundamental aspects of the immune system. Since 2016, Zoltan attended the yearly workshops organized by a group of theoretically inclined scientists (Figure 1), including two of the current associate editors of the Scandinavian Journal of Immunology (A.C. and Z.D.). Zoltan was known for his wit, erudition and clear grasp of issues at hand, and the group (represented by the authors of the obituary) grew fond of him. Let us all remember for what he was known in the past, and what we could learn from his experience. With this essay, we wish to remember Zoltan's accomplishment and achievement. Zoltan Nagy was an immunologist known for his scientific contributions to the genetic organization of the mouse major histocompatibility complex (MHC) and the biological function of both mouse and human MHC (H-2 and HLA). He was also arguably the only well-known research immunologist to have written a book on the history of contemporary immunology, entitled: ‘A History of Modern Immunology: The Path Toward Understanding’.1 Zoltan’s book struck many as an unusually candid and personal account of this history. This characteristic was perhaps because he felt himself, initially at least, to be an outsider. He was trained as a veterinarian at the University of Budapest, and his first job was as a pathologist at the Veterinary Medical Research Institute, of the Hungarian Academy of Science. Being unhappy with such a fate for the rest of his life, he took a leave to become a Member of the Basel Institute of Immunology for two years, from 1974 to 1976. The decision to apply and become a member of the Basel Institute required, as he indicates in his book, considerable braveness, but allowed him to realize his aspirations and overcome his feelings of intimidation. Zoltan had an obvious literary flair, evident to any reader of his History. He invented a character, Dr. G, who is offstage for most of the time, as the author describes advances in the field and briefly who was responsible for these. Dr. G then sometimes appears on stage, in a different print, to give his thoughts on the plausibility and significance of the findings just described, as well as some of the characteristics of the personalities involved. As he said in the introduction of his book, ‘Ideally a scientist is a person who is blessed (or damned) with a restless mind, and an overdose of curiosity, which literally force him/her to keep asking all those What? Why? And How? questions that down-to-earth people only ask in their childhood’. Perhaps the most significant word in this quote is the first, ‘Ideally’. Dr. G muses on the pertinence of the role of various human frailties of various participants in the history of the subject. He thus reflects on the subjective aspects of science, such as how the role of charisma of a proponent affects the acceptability of an idea. Naturally, such a style in turn has its subjective side. Zoltan pays attention primarily to people whom he met and got to know. Zoltan had a deep interest in the philosophy of science. For example, he, through Dr. G, describes in his book ‘two camps with diagonally opposite attitudes to science: one camp could be called “reductionists”, their goal is to extract a concept from the data, and they don’t mind losing details that appear peripheral to the concept. On the other side are the “complicators” who consider every detail equally important, irrespective of whether it seems to make sense or not, as they believe that any data could become the key to solving a problem’.1 Zoltan’s career after the Basel experience attests to the breadth of his aspirations. He was a visiting Associate Professor at Queens University, Ontario, Canada, on a fellowship to do cancer research, for two years (1978-1979). He returned to Europe as Deputy Director of the Max Planck Institute for Biology at Tübingen, under the Directorship of Jan Klein (1979-1982). He then appears to have been inspired to realize the benefits of basic research for the well-being of mankind. He became a Project Leader, Sandoz Pharmaceutical Inc., Basel, Switzerland (1985-1992), then took up a similar post in the Department of Inflammation, Hoffmann-La Roche, Nutley, New Jersey, 1992-1995, and became Head, Department of Immunology, of this organization, in 1995. Scientifically, Zoltan’s early days at Basel and Tübingen were influenced by his ambition to understand how immune responses are controlled. He and his group used the tools of cellular immunology and the variety of inbred mouse strains available to identify genes that control the immune response to various antigens. These contributed to a better understanding of the MHC and their immune response (Ir; ie I-A and I-E in mice, and HLA-DR, HLA-DP and HLA-DQ in human) genes. In particular, Zoltan was the last author of the Nature paper in1981, where the definition of MHC class I and class II was introduced.2 Nowadays, it is common ground, but that Zoltan and Jan Klein were the originators was mainly forgotten. Following the discovery of the T cell receptor (TCR), he became fascinated by the molecular targets of T cell recognition: antigenic peptides in the grooves of the MHC molecules. He was very proud that these peptides and especially the motifs defining their specificity for MHC molecules were identified by his former PhD student (and co-author H-G.R.). Remarkably, H-G.R. returned to the Max Planck Institute in Tübingen as a group leader in 1987 and then worked again in Zoltan's former laboratory. Thus, H-G.R. found himself at the very same place where he learnt so much about the role of MHC in the interaction of antigen with T cells, a field which was muddy at the time Zoltan was in Tübingen. There were many discussions about the nature of T cell recognition of MHC plus antigen, in particular an idea called ‘determinant selection’,3 which essentially meant that MHC somehow binds antigen. Studying the interaction of T cells with antigen in various contexts afforded a better insight into T cell recognition, as the initial event of the immune response. Zoltan and his colleagues contributed to the understanding of the immunodominance of T cell determinants, and the role of in vivo competition between self-peptides and foreign antigens in T cell activation.4-6 Moreover, Zoltan and colleagues showed plasticity of T cell repertoire. Bovine insulin–specific MHC I-Ab–restricted CD4 T cell clones derived from H-2b mice (C57BL6; B6) expressed the TCR V beta 6 gene in a large proportion. Since in (B6 x DBA/2)F1 mice the V beta 6+ T cells are deleted by self-tolerance to Minor lymphocyte stimulating (Mls)-1a antigen, the majority of insulin-specific T cell clones derived from the latter strain (H-2b x H-2d) expressed other V betas without change in their fine specificity. Thus, in a potential autoimmune setting exemplified by the insulin-specific response, the shift in TCR usage caused by self-tolerance to Mls-1a was fully compensated, demonstrating avid T cell repertoire flexibility.7 Further, he and his colleagues investigated the role of HLA-DR in susceptibility to autoimmune diseases. Zoltan and coworkers generated transgenic mice with HLA-DRA-IE alpha and HLA-DRB1*0401-IE beta chimeric genes and demonstrated that a human MHC class II peptide–binding site alone could confer susceptibility to experimental allergic encephalomyelitis, a mouse model for multiple sclerosis.8 Finally, Zoltan pioneered the development of synthetic peptides that could potentially be used as MHC-selective antagonists of antigen presentation in the treatment of autoimmune diseases such as diabetes and rheumatoid arthritis.9, 10 Zoltan’s book was obviously a testament to his experiences as a scientist. Thus, his fascination with the MHC gives the book a slant, and the history he recounts again reflects the people he met and interacted with. However, there is an overriding theme to the book written, it appears, as one looking back over his life. He makes the case, often via Dr G, that the field would be well served if more extensive interactions could be facilitated between those experimentally and theoretically inclined. It was because of this assessment that he was invited to an annual one-week workshop, of similarly inclined individuals, on the foundations of immunology and their pertinence to medicine, initiated in 2016 (Figure 1). The writers of this obituary, with the exception of H-G.R., are members of this workshop. The whole group has published their ideas, discussions and accomplishments as discussion forum articles in the Scand J Immunol over the past several years.11, 12 Data sharing is not applicable to this article as no new data were created or analyzed in this study.

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