Evolution in microcosm: the rapid somatic diversification of lymphocytes

The characteristic task of the immune system is learning to respond specificially to entirely novel antigens. How it may do this is discussed under 6 headings. 1. -- Vertebrate and invertebrate immune strategies are contrasted. Whereas among invertebrates whole individuals appear to be selected for their immunological fitness, vertebrates have developed an internal population of lymphocytes among which variants arise and are selectively stimulated by antigen to give a response which protects the "host". 2. -- The genetic mechanism underlying this variation of lymphocytes is of great interest, but its discovery will not, given present ignorance of eukarote DNA, answer those questions about variation at the phenotypic level which are vital to the rest of immunology: e.g. when, how fast, and under what conditions do variantes arise? 3. -- A great deal of indirect evidence suggests that the production of entirely new variant lymphocytes occurs throughout life, particularly after antigenic stimulation. 4. -- Experimental approaches are discussed which might provide direct evidence for or against the idea of rapid variation among stimulated lymphocytes. The method used was based on detecting the cross-reactive specificity of antibody produced by single cells. 5. -- Evidence obtained with this technique is briefly described. There were two main kinds of experiment. In the first, rapid variation (at the rate of about one variation event per 30 divisions) was demonstrated within single clones of proliferating antibody-forming cells. In the second group of experiments, it was shown that certain uncommon antibody-forming cell specificities present at the peak of a primary response were entirely absent at earlier stages. 6. -- A new immunological paradigm may emerge from work on the generation of diversity and on active control of response. There may be relatively few types of lymphocytes with germ-line-coded receptors. These are stimulated by environmental antigens and mitogens, and perhaps by self stimulated by environmental antigens and mitogens, and perhaps by self antigens. Extensive proliferation and variation occurs, which in turn elicits suppressor reactions directed against antigen or against idiotypes of responding clones. The immune repertoire of the adult vertebrate is a product of the evolution of its lymphocytes under the competing pressures of antigenic stimulation and active suppression.