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 specific. 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, despite minimal structural identity, to elicit cross-reactive proliferative responses at the bulk T cell level. This epitopic mimicry was also observed when peptide (CS.T3_378-395 and TT_830-844)-specific CD4⁺ T cell lines and T cell hybridoma clones were used in proliferation and Ag presentation assays. A scrambled CS.T3_378-395 peptide did not show any proliferation, indicating that the specificity of the cross-reactive responses may be linked with the primary structure of the peptides. Blocking of CS.T3_378-395-specific CD4⁺ T cell proliferation by anti-MHC class II mAb showed that recognition of promiscuous T cell epitopes is largely in association with MHC class II molecules. These findings suggest that promiscuous Th epitopes may be useful in designing peptide-based vaccine constructs. At the same time these results show that at the T cell level there may be a great deal of immunological cross-reactivity between heterologous pathogens, and because of this the host's response to a pathogen may be modified by its previous experience with other unrelated pathogens.