Peptide register shifting within the MHC groove: theory becomes reality

Anatomy of T cell autoimmunity to myelin oligodendrocyte glycoprotein (MOG): Prime role of MOG44F in selection and control of MOG‐reactive T cells in H‐2b mice

“…Several molecular mechanism(s) could provide a basis for such multiple TCR-recognition modalities of MOG37-52/A b . One is the possibility that MOG37-52 may harbor different sequential and/or overlapping core epitopes ("register shifting" [50]), each of which can select different TCR. An alternative is that different non-MHCbinding residues of MOG40-48 may serve as major TCRcontact residues to drive the selection of different TCR.…”

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].…”

“…It is thus possible that a peptide, which contains multiple predicted anchor residues, might slide forward and backward in the MHC class II groove, assuming different binding registers, only one of which is optimal for the recognition by a specific TCR. This is called peptide register shifting within the MHC groove [19][20][21][22] and may represent an additional element that contribute to the difficulty in detecting CD4 1 T cells by MHC class II tetramers because it would result in the generation of tetramers with each arm made of a different peptide-MHC conformer. This, in turn, would decrease the overall avidity of the peptide-MHC class II tetramer for its cognate TCR, which would fall below a threshold compatible with the binding of soluble tetramers to the specific T cells.…”

“…The peptide-binding groove of MHC class II molecules is opened at both ends, allowing peptides with multiple P1 anchor residues to bind in different registers into the groove [22]. We hence hypothesized that a peptide with multiple P1 anchor residue can bind into the groove of each HLA-DR Ã 1101 monomer with different registers, generating heterogeneous peptide-tetramer conformers endowed with decreased avidity for their cognate TCR.…”

“…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.…”