Flexibility in MHC and TCR recognition: Degenerate specificity at the T cell level in the recognition of promiscuous th epitopes exhibiting no primary sequence homology

Recognition of peptide Ags by T cells through the TCR can be highly specifi c. In this report we show the degeneracy of Ag recognition at both MHC and TCR levels. We present evidence that unrelated promiscuous Th cell epitopes from various protein sources exhibit sufficient structural homology, despi te minimal structural identity, to elicit cross-reactive proliferative resp onses at the bulk T cell level. This epitopic mimicry was also observed whe n peptide (CS.T3(378-395) and TT830-844)-specific CD4(+) T cell lines and T cell hybridoma clones were used in proliferation and Ag presentation assay s. A scrambled CS.T3(378-395) peptide did not show any proliferation, indic ating that the specificity of the cross-reactive responses may be linked wi th the primary structure of the peptides. Blocking of CS.T3(378-395)-specif ic CD4(+) T cell proliferation by anti-MHC class II mAb showed that recogni tion of promiscuous T cell epitopes is largely in association with MHC clas s II molecules. These findings suggest that promiscuous Th epitopes may be useful in designing peptide-based vaccine constructs. At the same time thes e results show that at the T cell level there may be a great deal of immuno logical cross-reactivity between heterologous pathogens, and because of thi s the host's response to a pathogen may be modified by its previous experie nce with other unrelated pathogens.