A highlight of his immunology career was the way he tackled major questions in a rigorous way. For instance, he identified functional subpopulations of T cells using one of the first monoclonal antibodies — the W3/25 antibody that was later shown to recognize rat CD4. This antibody was the result of a collaboration between César Milstein in Cambridge and Alan Williams in Oxford in 1975. It was one of the first monoclonal antibodies to be used to identify new cell surface proteins, and the combination of monoclonals and cell sorting went on to become a standard immunological research approach. Don helped to show that W3/25 could inhibit mixed lymphocyte reactions in vitro — the first functional effect demonstrated for a mAb — and subsequently applied the treatment in vivo, showing it was also effective in inhibiting a rat autoimmune model of multiple sclerosis. Those early experiments highlighted the potential of immunotherapy with monoclonal antibodies to treat disease, which is now widely used in the clinic. Further analysis of subpopulations showed that the CD4+ T cells could be split into functionally distinct populations using antibodies specific for high molecular weight isoforms of CD45, which is the strategy still routinely used today to delineate subpopulations of human T cells. These studies led to the identification of two distinct populations of CD4+ T cells, one that mediated immune responses and another that actively controlled those responses, now known as regulatory T cells. Don’s work represented some of the foundational studies in the regulatory T cell field, a large and active area in current immunological research. Don never forgot his physics training, which afforded him a unique quantitative perspective on biological problems that was rare among biologists at the time. The importance of an interdisciplinary approach in the biological and physical sciences is now well recognized and applied. He used novel mathematical approaches to understand the functional heterogeneity of lymphocyte populations and, later, applying simple quantitative principles, published a theoretical paper arguing that the specificity of the T cell receptor had to be broadly cross-reactive and not highly specific, as was widely presumed at the time. This paper has been cited more than 700 times and, remarkably, after more than 20 years, is still cited more than 30 times a year, a testament to the enduring quality of Don’s work, which continues to influence immunologists today.
Don ran a small but effective research group, training students and post-docs over many years. His combination of intellectual rigor, empathy and humility created a positive and nurturing research culture that was highly influential for his mentees and colleagues alike. Many of his trainees left to become successful immunologists across the world, benefiting from the unique environment Don created. He was made an honorary life member of the British Society for Immunology in 2017.
