Dichotomy between the T and the B cell epitopes of the synthetic polypeptide (T,G)‐A–L

Abstract Studies with the well‐characterized, synthetic, random‐multichain polypeptide poly( L Tyr, L Glu)‐poly( DL Ala)–poly( L Lys) (T,G)‐A–L), led to the discovery of determinant‐specific genetic control of the immune response, as well as to other immunological phenomena. Moreover, the tetrapeptide TyrTyrGluGlu built on the same backbone (“T‐T‐G‐G)‐A–L”) was found to represent its major B cell epitope. We have recently shown that for interaction with major histocompatibility complex class II molecules and stimulation of T cells, (T, G)‐A–L requires proteolytic processing and the resulting T cell epitopes are close to the N termini of the branched polymer's side chains. Thus, we were interested to elucidate the major T cell epitope of (T, G)‐A–L, by using the ordered polypeptides (T‐T‐G‐G)‐A–L and (T‐G‐T‐G)‐A–L, in which only the two internal amino acids of the tetrapeptide attached to the side chains are switched. We established T cell lines to these antigens, and found that the ordered analog (T‐T‐G‐G)‐A–L, which was defined as the B cell epitope of (T,G)‐A–L, did not represent its T cell epitope, whereas (T‐G‐T‐G)‐A–L, to which only a minor anti‐(T,G)‐A–L Ab response was directed, was found to be its major T cell epitope. In addition, there was no cross‐reaction between (T‐G‐T‐G)‐A–L and (T‐T‐G‐G)‐A–L at the T cell level, similar to the lack of cross‐reaction of their antibodies. Analysis of the repertoire of the T cell receptors used by these lines revealed that the (T,G)‐A–L and the (T‐T‐G‐G)‐A–I specific T cell lines were not restricted in their Vα and Vβ TCR usage, whereas the (T‐G‐T‐G)‐A–L‐specific line was restricted by both Vα and Vβ T cell receptor gene products. This difference might be due to the thymus‐independent characteristics previously described for the latter antigen.