Recognition of multiple peptide cores by a single T cell receptor.

Abstract

SummaryWe present evidence that a single T cell clone can recognize at least five different overlapping peptides, each with its distinct core structure, in the context of the same major histocompatibility complex (MHC) molecule. Distinct core residues are crucial for triggering the T cell receptor (TCR) in each case. These results suggest that the TCR (a) has multiple sets of contact residues for alternative peptide-MHC ligands, the binding to any one of which can trigger the cell; and/or (b) is able to attach to the peptide-MHC complex in more than one orientation. In this sense, the TCR is a multisubsite structure capable of being stimulated by a variety of peptide ligands associated with the same MHC molecules.T CRs recognize an antigen only when the antigen's peptide fragments are lodged in a groovelike site on MHC molecules (1). How do the TCRs interact with the peptide-MHC complex? The answer is not clear because the crystal structure of the TCR-peptide-MHC complex still has not been solved. In the meantime, several models for the ternary molecular interaction have been proposed in which the CDR3 loops (encoded by the V-(D)-J junctional region) of both chains of the TCR molecule bind the nominal peptide, whereas the germline-encoded CDR1 and CDR2 loops bind the oe helices of the MHC molecule, which flank its peptidebinding groove (1-4).Using variants of each of the three participating molecules of the TCR-peptide-MHC complex, extensive attempts have been made to test these predictions (4-9). The results from these studies have neither entirely supported nor contradicted these models; nevertheless, several characteristics of the interacting trimolecular complex have emerged. It thus seems clear that a single peptide-MHC ligand can induce several distinct TCR molecules, with each TCR molecule recognizing a distinct aspect of the peptide in the MHC groove. Different TCR molecules displaying specificity for the same peptide-MHC ligand may interact with different and overlapping residues of the peptide (4-8). In addition, studies with MHC mutants at the residues pointing inward along the wall of the peptide-binding groove of the MHC molecule showed that different TCRs displaying identical specificity for the ligand were differentially affected by such mutant MHC molecules (8). These results emphasize that alterations of the particular conformation of the peptide-MHC complex, induced by the association of the peptide with the altered peptidebinding groove, can result in loss of recognition. Taken together, these results indicate strict constraints in interactions between the TCR molecule and the peptide-MHC complex.However, how precise are the requirements for peptide structure, distribution of charge and hydrophobicity for a peptide to be a stimulatory one for a given TCR? Can only a single sequence from the antigen associated with a given MHC molecule meet the constraints of TCR recognition? We have asked this question by using a previously reported panel of I-A arestricted sperm whale myoglobin (SWM) 1 peptid...

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

“…Kinetic and thermodynamic studies also provide evidence that the TCR and/or peptide-MHC have flexible binding surfaces that stabilized upon binding and suggest that conformational flexibility may contribute to cross-reactivity in Ag recognition, as observed in the present study (45). On the other hand, in a study in which a single T cell clone could recognize at least five different peptides, it was suggested that the TCR may have multiple sets of contact residues for different peptide/MHC ligands, binding to any one of which can trigger the cell, and/or that the TCR could interact with the peptide/MHC complex in more than one orientation (9). It is therefore likely that several peptide sequences may satisfy the requirements of TCR recognition once they have crossed the hurdle of MHC binding with appropriate affinity.…”

“…Similarly, while eight identical residues were required in the recognition of a human HLA-DQ-restricted clone by two different T cell epitopes from mycobacterial heat shock protein 65 and the human heat shock protein 60 (35), only two unique residues were sufficient for the recognition of an HLA-DR1-restricted T cell clone by a peptide from the influenza virus hemagglutinin (36). Extreme cases of T cell cross-reactivity involving peptides without any apparent sequence homology have also been recently reported (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)37). For example, Bharadwaj et al observed degenerate recognition of a chimeric peptide based on MBP by cloned T cells (2).…”

“…1). However, several recent observations reveal that the TCR is highly flexible in its recognition, as it can recognize large number of different peptides that do not necessarily show strong sequence homology (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). It has become clear that a high level of degeneracy in TCR recognition is necessary to produce an adequate TCR repertoire capable of responding to the universe of pathogens as well as for the survival of T cells (reviewed in Ref.…”

The CD4+ T‐cell epitope‐binding register is a critical parameter when generating functional HLA‐DR tetramers with promiscuous peptides

“…On the other hand, it is also possible that a single peptide containing multiple anchors might bind a single MHC class II allele with distinct registers and thus generate different antigenic MHC class II-peptide conformers, each recognized by a specific set of TCR [20,22,45].…”

“…As described by James et al [44], promiscuous peptides that bear different anchors were found to contain multiple epitopes, each binding in a monogamous way a specific HLA-DR allele. Therefore, these peptides do not represent real promiscuous epitopes, but rather a linear array of different monogamous epitopes.On the other hand, it is also possible that a single peptide containing multiple anchors might bind a single MHC class II allele with distinct registers and thus generate different antigenic MHC class II-peptide conformers, each recognized by a specific set of TCR [20,22,45].In line with this observation, our data are consistent with the possibility that the MAGE-A3-derived p57 and p58 peptides, which are predicted to contain different putative P1 anchors for the HLA-DR Ã 1101 allele, bind into the HLA-DR groove in different registers, generating different peptide-HLA-DR conformers. By reducing the number of putative anchor residues predicted in the promiscuous peptides, therefore minimizing the number of different registers that the peptide can assume into the MHC class II groove, we show that it is possible to generate functional HLA-DR Ã 1101 tetramers that bind the specific TCR.…”