A tale of two peptides, TyrTyrGluGlu and TyrGluTyrGlu, and their diverse immune behaviour

Studies on a synthetic multichain polypeptide antigen, (T,G)-A--L, prepared by polymerization techniques, led to a better understanding of the molecular basis of antigenicity, and of many other immunological phenomena, as well as to the discovery of determinant-specific genetic control of immune response. In view of the intensity of studies with this polymer, we were interested in elucidating its major B and T cell epitopes. We investigated two tetrapeptides, TyrTyrGluGlu and TyrGluTyrGlu. Both were attached to multichain branched poly(DLalanine). Even though the two resulting synthetic immunogens are essentially identical in their molecular weight, size, shape and composition, and differ chemically only in the sequence of the tetrapeptide epitopes, the immunological differences observed were profound. Antibodies in the two systems do not cross-react. The major B cell epitope of (T,G)-A--L is TyrTyrGluGlu, whereas the major T cell epitope is TyrGluTyrGlu. The two antigens are under different genetic controls, and differ in their uptake by macrophages. The TyrTyrGluGlu polymer is thymus-dependent, whereas the TyrGluTyrGlu polymer is thymus-independent. Investigation of the two tetrapeptides in their polymeric form, by photochemically induced dynamic nuclear magnetic polarization techniques, shows that they differ strongly in their intra-epitope aromatic interactions. Phenolic groups in TyrGluTyrGlu interact with each other, whereas they are far apart in TyrTyrGluGlu, as seen also in computer-derived models.