Re-Directing CD4+ T Cell Responses with the Flanking Residues of MHC Class II-Bound Peptides: The Core is Not Enough

Abstract

Recombinant αβ T cell receptors, expressed on T cell membranes, recognize short peptides presented at the cell surface in complex with MHC molecules. There are two main subsets of αβ T cells: CD8+ T cells that recognize mainly cytosol-derived peptides in the context of MHC class I (pMHC-I), and CD4+ T cells that recognize peptides usually derived from exogenous proteins presented by MHC class II (pMHC-II). Unlike the more uniform peptide lengths (usually 8–13mers) bound in the MHC-I closed groove, MHC-II presented peptides are of a highly variable length. The bound peptides consist of a core bound 9mer (reflecting the binding motif for the particular MHC-II type) but with variable peptide flanking residues (PFRs) that can extend from both the N- and C-terminus of the MHC-II binding groove. Although pMHC-I and pMHC-II play a virtually identical role during T cell responses (T cell antigen presentation) and are very similar in overall conformation, there exist a number of subtle but important differences that may govern the functional dichotomy observed between CD8+ and CD4+ T cells. Here, we provide an overview of the impact of structural differences between pMHC-I and pMHC-II and the molecular interactions with the T cell receptor including the functional importance of MHC-II PFRs. We consider how factors such as anatomical location, inflammatory milieu, and particular types of antigen presenting cell might, in theory, contribute to the quantitative (i.e., pMHC ligand frequency) as well as qualitative (i.e., variable PFR) nature of peptide epitopes, and hence offer a means of control and influence of a CD4+ T cell response. Lastly, we review our recent findings showing how modifications to MHC-II PFRs can modify CD4+ T cell antigen recognition. These findings may have novel applications for the development of CD4+ T cell peptide vaccines and diagnostics.

Combination of In Silico Methods in the Search for Potential CD4+ and CD8+ T Cell Epitopes in the Proteome of Leishmania braziliensis

“…As more hydrogen bonds are formed between the receptor and the predicted epitope, the Isc value is lower, i.e., the complex has a higher binding affinity, emphasizing the fact that the peptides bind to the MHC alleles (particularly MHC II) via an “extensive hydrogen bond network” (28). To further investigate this correlation, three complexes included in the final results (FPD500) were selected and analyzed (Figure 6).…”

Identification of peptides with tolerogenic potential in a hydrolysed whey‐based infant formula

“…Only peptides containing at least nine AAs were taken into account, as this is the minimal size for binding to MHC class II molecules and subsequent T cell recognition. 16…”

Improved methods for predicting peptide binding affinity to MHC class II molecules

“…However, it has been shown that peptide flanking regions (PFRs) on either side of the binding core affect peptide-MHC binding and, thereby ultimately also influence the peptide immunogenicity. 7,9 There are therefore many factors that make it difficult to predict peptide binding affinities to MHC-II molecules, including the polymorphic nature of MHC-II molecules, the variations in peptide length, the influence of the PFRs and the identification of the correct peptide binding core. All these factors complicate the task of predicting peptide binding affinities to MHC-II molecules; most methods therefore still have a low performance compared with MHC class I (MHC-I) peptide binding prediction methods.…”