ANTIGENICITY OF GLOBULAR PROTEINS

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To gain a better understanding of the antibody response to a T cell dependent globular protein antigen, a range of T cell hybridomas and B cell hybridomas have been developed that react to the well-studied major antigenic determinant of pigeon cytochrome c. Following the demonstration that T cells respond only to peptide fragments of the protein and that all naive B cells, regardless of their specificity, can be stimulated to antibody synthesis by soluble factors produced by activated T cells, the biology of this system can now be described at the molecular level. Cytochrome c is a particularly effective choice as an antigen, since the chemistry of the protein is well known and it is possible to obtain material of any desired primary structure with the needed radioactive, fluorescent and photoaffinity labels. With such ligands it is intended to study quantitatively the binding of T cell antigenic peptides and cell surface Class II molecules to T cells, resulting in their activation. Similarly, the synergistic bindings of B cell growth and differentiation factors, produced by activated T cells, and of B cell antigen (the intact native protein), to B cells, causing them to proliferate and mature to antibody secreting cells, will be examined quantitatively. The mechanisms by which the cells of the immune system interact by binding to their physiological external ligands, being thereby activated to produce the set of growth factors which will enable the next cell type in the system to be activated by its external ligands to growth and differentiation in a controlled fashion, present an excellent and readily analyzable model for the relation of growth factors to cell growth in general, and of the disturbances that may occur in that relation. The recent demonstration tha the putative transforming proteins of oncogenic viruses are structurally related to growth factors or to their cell surface receptors, provides several possible mechanisms whereby tumorigene is may result from a change in the normal physiological relation of growth factors and their specific cellular receptors. For example, whether certain lymphoid tumors, such as B cell leukemias, result from the production of abberant growth factors or from receptors that have lost normal control sequences, or from receptors that bind and react to the B cell growth factor but can no longer bind or react to the B cell differentiation factor, will be straightforward to determine once the modalities of binding of lymphocytes of the immune system to their physilogical ligands will have been analyzed, as proposed in this study.