Unipotentiality of lymphoid cells

The most fundamental tenet of the clonal selection hypothesis, and that which distinguished it from all others, was 'the existence of multiple clones of globulin-producing cells, each responsible for one genetically determined type of antibody globulin'. Indeed, in discussing the implication of the theory, Burnet stated 'the clonal selection hypothesis would be completely validated if it could be shown that single cells from a non-immune animal gave rise to clones, each cell of which under proper physiological conditions contained, or could liberate, antibody-type globulin of a single pattern or at most of a uniform small range of patterns'. Early efforts to test this postulate were hardly supportive. Attardi, Hora-bita, Lennox and Cohn concluded, from single-cell studies of phage-specific antibodies, that single cells were multipotential. Studies from a variety of laboratories, including those of Cunningham, Liacoupoulus, Hiramoto and Sercarz, appeared to demonstrate multiple antibodies per single cell. Additionally, Burnet's own experiments, using a tissue reactivity test devised by Simonsen, were incompatible with a highly diverse repertoire of unipotential cells. However, in retrospect, each of these anomalous findings has been attributable to experimental artifact, the capacity of certain antibodies to bind numerous antigens (multispecificity), or, as in the case of the Simonsen assay, an inordinately high frequency of T cell responses to any given major histocompatibility complex (MHC) alloantigen.

In addition, the numerous examples of the homogeneity of immunoglobulins produced by multiple myeloma cells and the existence of restricted antibody responses to certain antigens, such as Krause's demonstration of restricted antibodies in rabbits responding to A-carbohydrate, implied that the product of single antibody-forming cell clones was homogeneous. A similar conclusion was drawn from findings of numerous laboratories, including those of Nossal, Mâkelà and Biozzi, that single cells bound only one antigen. Using the splenic focus assay, where single antigen-specific precursor cells were isolated in cultures of splenic fragments, Klinman demonstrated, in 1969, the homogeneity of the antibody product of the clonal progeny of a single stimulated precursor cell (Figure 1). These studies demonstrated, by the homogeneity of antigen binding as well as heavy (H) and light (L) chain recombination analyses, that the product of antibody-forming cell clones was homogeneous and displayed binding characteristics that, in composite, could account for the affinity and heterogeneity characteristics of

Figure 1 Hapten binding curves constructed from equilibrium dialysis at 7°C with a) antibody from two antibody forming cell clones (foci) generated in splenic fragments, focus No. 1434 (•) and focus No. 2560 (■); and b) pooled antibody from the clonal progeny of numerous secondary B cells (o). r represents the moles of a, N-(3H)-acetyl-8-DNP lysine bound per mole of antibody at the equilibrium free hapten concentration, c. Antibody concentrations were determined at each point by radioimmunoassay and points represent duplicate samples which agreed to within 5%.

Figure 1 Hapten binding curves constructed from equilibrium dialysis at 7°C with a) antibody from two antibody forming cell clones (foci) generated in splenic fragments, focus No. 1434 (•) and focus No. 2560 (■); and b) pooled antibody from the clonal progeny of numerous secondary B cells (o). r represents the moles of a, N-(3H)-acetyl-8-DNP lysine bound per mole of antibody at the equilibrium free hapten concentration, c. Antibody concentrations were determined at each point by radioimmunoassay and points represent duplicate samples which agreed to within 5%.

serum antibodies. Although these particular studies used B cells from previously immunized mice, subsequent studies extended these findings to B cells from nonimmune mice, thus fulfilling Burnet's requirements. The only exception to the homogeneity of the antibody produced by single clones was the production of multiple isotypes by most clones; however, Gearhart and Klinman demonstrated that antibodies of different isotypes generated from the same clone shared variable regions. In recent years, the molecular mechanisms that account for the sorting of unique specificities to individual lymphocytes have become well documented and are discussed elsewhere in this volume.

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