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

Abstract

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.T3378–395 and TT830–844)-specific CD4+ T cell lines and T cell hybridoma clones were used in proliferation and Ag presentation assays. A scrambled CS.T3378–395 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.T3378–395-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.

Gag- and Nef-specific CD4+T cells recognize and inhibit SIV replication in infected macrophages early after infection

“…more sequence diversity in their target epitopes (33,34). In support of this notion, dengue virus-specific CD4 ϩ T cells have been reported to recognize epitope variants not only from other dengue viruses, but even other flaviviruses (35).…”

Depletion of naive T cells using clinical grade magnetic CD45RA beads: a new approach for GVHD prophylaxis

“…15 As memory T cells have the capacity of rapid expansion upon secondary Ag challenge, the formation of alloreactive memory T cells could have serious consequences in terms of GVHD. Presensitization would be a particular problem if pathogen-specific T cells with cross-reactivity to alloantigens are triggered by encounter with infectious agents.…”

Degenerate TCR recognition and dual DR2 restriction of autoreactive T cells: Implications for the initiation of the autoimmune response in multiple sclerosis

“…In order to study the TCR specificity repertoire of biologically relevant, in vivo expanded TCR deg TCC, our future studies will utilize TCR spectratyping of DR2-APM-reactive TCL and TCC to identify the in vivo expanded TCR deg TCC [17]. In addition to TCR degeneracy, conformational changes (involving TCR CDR3 loops and VaVb domain orientation) may contribute to the TCR's ability to adapt to structurally different peptides [18,19].…”