The clonal selection theory of acquired immunity

The clonal selection theory of acquired immunity Frank Macfarlane Burnet, along with David Talmage, developed a central concept in immunology that has lasted nearly 50 years. The clonal selection theory describes the mechanism by which immune cells can generate memory to a specific antigen. The development of immunity to a given infectious agent was an accepted concept but the way immune memory operated remained a mystery for many years. Central to the clonal selection theory was the generation of antibody responses to injected antigens. Each antibody recognises a specific antigen but it was unclear as to how the antigen initiated an antibody response. In the 1930-40’s it was known that a huge variety of antibodies existed, capable of recognising any given antigen. The ‘instruction theory’ was borne to explain this in chemical terms. It was thought that antigens acted as molecular templates for the production of antibody molecules. However, this chemical approach could not explain immune memory. It was later suggested that affinity for antigen was an inherent property of the immune system and the antigen was ‘selecting’ for those antibodies that already existed. Burnet and Talmage manipulated this idea of selection and realised that it was the cell producing the antibody that was selected. We now know that antibodies are produced by B cells and it was these lymphocytes that formed the basis of clonal selection. Burnet explained the phenomena of antibody specificity in terms of his clonal selection theory in 1957. He deduced that the antibody repertoire was produced spontaneously by cells without any dependence on external antigen. That when an antibody bound to the surface of a B cell encounters antigen, only those antibodies with sufficient specificity bind that antigen and hence activate the B cell. He then concluded that only those B cells specific for the antigen proliferate and produce antigen-specific antibodies. In effect, the B cell is selected on the basis of its antigen specificity and, through cell division, produces multiple clones of its self. Importantly, some of those B cell clones become memory cells so that when the antigen is encountered at a later date clonal expansion of specific memory B cells can take place and eliminate the antigen. Immune recognition and the expansion of specific B cells is the fundamental basis of immune memory and acquired immunity. The clonal selection theory was a pivotal landmark in immunology, but raised many more questions. How are B cells prevented from producing antibodies directed against self tissue? Peter Medawar demonstrated that tissue transplanted from a donor to a host was rejected, while tissue transplanted from the same host was accepted. The immune system somehow recognises the donor tissue as foreign (non-self) and its own tissue as self. However, non-identical bovine foetuses connected in utero share blood during development. Although they should recognise each other as ‘foreign’ they are unable to respond to each other’s tissue. This demonstrated that immune specificity was somehow learned and not a result of predetermined genetics. The simple explanation for this is that during B cell development those B cells expressing antibodies that recognise self molecules are eliminated from the B cell pool and those with affinity for non-self survive. The clonal selection theory can also be applied to the T cell system. T cells recognise antigen in a similar way to B cells, although this antigen has been processed into small peptides. Similarly, during T cell development those T cells that recognise self peptides are killed and only those capable of recognising foreign peptides survive. This process is also referred to as tolerance to self. How is the vast antibody repertoire generated? Like all proteins, antibodies are produced by genes. However, there are many more antibodies than there are genes. Therefore there must be a mechanism in place to generate diversity.Actually two mechanisms exist, the first being somatic mutation. Random nucleotide substitutions within antibody genes occur at the very point that translates to the antigen binding site, introducing a certain amount of variation. The other mechanism is known as genetic recombination. Antibody genes comprise three separate elements, all of which must combine to form a complete gene. Furthermore, each of these elements has many different versions so that any version of one element can recombine with any version of another element. This process is largely stochastic so that recombination results in the random generation of a large diversity of antibody molecules and hence a huge B cell population. The same mechanism occurs when generating T cell receptors. This totals to a highly variable immune cell repertoire capable of recognising a million million different antigenic motifs. The clonal selection theory has evolved over the past 50 years and has been supplemented by new hypotheses. Of note, the ‘self versus non-self’ discrimination model has been expanded to include recognition of evolutionary conserved molecules expressed by microbes, while the ‘danger model’ of immune recognition states that immunity is only generated against a foreign antigen if accompanied by a ‘danger signal’. Instead of replacing the clonal selection theory these new hypotheses complement Burnet’s original thesis. Frank Macfarlane Burnet and Peter Medawar were awarded the Nobel Prize in Physiology or Medicine in 1960.