Antigen‐specific clone selection in vivo

Abstract

THYMUS NEGATIVE SELECTION In 1959–1961, I was far from Burnet’s influence studying the pathogenesis of virus-induced mouse leukaemia in London, UK. As a result of this work, I discovered the immunological function of the thymus.1 How that came about has been recounted elsewhere.2 Grafting thymus tissue reversed the immune defects of neonatally thymectomized mice but when thymus came from a strain of mice allogeneic to the thymectomized recipients, these were able to reject skin grafts from the allogeneic strains tested but not from the thymus donor strain (Figure 1). This led me to suggest, ‘when one is inducing a state of immunological tolerance in a newly born animal, one is in effect performing a thymectomy, not a complete thymectomy but a partial, selective or immunological thymectomy. In accordance with selective theories of antibody formation, injected antigenic material might make contact with certain cell types differentiating in the thymus and in some way prevent these cells from maturing to a stage when they would be capable of reacting immunologically.3 In other words, the thymus could negatively select antigenspecific clones in vivo and might be the seat where self-tolerance was induced. It was, therefore, a great surprise to me when Burnet asked me to see him during his visit in London in early 1962 and I was immensely pleased to show him the thymus graft results that were in press in the Proceedings of the Royal Society.3 He was, at that time, one of the few immunologists convinced of the immune function of the thymus, as was evident in the lecture he later gave in London.4 The finding that thymus-deficient mice were much more prone than normal mice to develop tumours after treatment with certain carcinogenic chemical agents and oncogenic viruses5,6 provided some experimental support for Burnet’s concept of immunological surveillance.7 Although T cells can, in some experimental situations, act as killer cells against tumour cells, I believe that if tumour antigens do cross-react with self-antigens that are ectopically expressed in thymus medullary epithelial cells, one will not be able to prime the immune system to these antigens.2 POSITIVE SELECTION OF ANTIGEN-SPECIFIC T-CELL CLONES In 1966, I headed the Experimental Pathology Unit of the Walter and Eliza Hall Institute of Medical Research following the invitation of the then director, Gustav Nossal. With my first PhD student, Graham Mitchell, we gathered more evidence for in vivo selection of antigen-specific clones. As admirably recounted by Graham Mitchell in this symposium,8 we used genetically marked cells and adoptive transfer to established unequivocally and for the first time: (a) that thymusderived cells could be activated specifically by antigen9 (b) that they were not the precursors of antibody-forming cells,10,11 (c) that they were essential to help, via some type of collaboration, other lymphocytes derived from bone marrow to respond to antigen by producing antibody.11 These results were initially greeted with surprise and scepticism (for example, ref12), a common criticism being that two rare, clonally individuated