The relationship between class I binding affinity and immunogenicity of potential cytotoxic T cell epitopes.

Abstract

The relationship between binding affinity for HLA class I molecules and immunogenicity of discrete peptide epitopes has been analyzed in two different experimental approaches. In the first approach, the immunogenicity of potential epitopes ranging in MHC binding affinity over a 10,000-fold range was analyzed in HLA-A*0201 transgenic mice. In the second approach, the antigenicity of approximately 100 different hepatitis B virus (HBV)-derived potential epitopes, all carrying A*0201 binding motifs, was assessed by using PBL of acute hepatitis patients. In both cases, it was found that an affinity threshold of approximately 500 nM (preferably 50 nM or less) apparently determines the capacity of a peptide epitope to elicit a CTL response. These data correlate well with class I binding affinity measurements of either naturally processed peptides or previously described T cell epitopes. Taken together, these data have important implications for the selection of epitopes for peptide-based vaccines, and also formally demonstrate the crucial role of determinant selection in the shaping of T cell responses. Because in most (but not all) cases, high affinity peptides seem to be immunogenic, our data also suggest that holes in the functional T cell repertoire, if they exist, may be relatively rare.

Immunity to CRISPR Cas9 and Cas12a therapeutics

“…Black bars at the bottom of each panel depict residue positions of peptide sequences that are predicted to bind more than half of the reference HLA class I allotypes. (b) HLA class II‐binding peptide sequences within Cas9 and Cas12a proteins were predicted with the consensus method hosted on the IEDB 3.0 server using default settings. Twenty‐seven reference HLA class II allotypes (rows) were used for the prediction.…”

“…Predicted T‐cell epitopes on Cas9 and Cas12a (Cpf1) proteins. (a) HLA class I‐binding peptide sequences within Cas9 and Cas12a (Cpf1) proteins were predicted with the consensus method hosted on the IEDB 3.0 server using default settings. Twenty‐eight reference HLA class I allotypes (rows) were used for the prediction along the entire length of the Cas9 or Cas12a proteins, and the predicted propensities of peptide binding to each HLA class I allotype are denoted in red (column).…”

“…Generally, higher binding stability of a peptide to the HLA binding groove increases the probability that the peptide will be presented as an antigen, thereby also increasing the probability that the peptide will elicit a T-cell response. [159][160][161] Benchmarking of HLA-binding prediction algorithms reveals that they can be reasonably accurate for the most well-studied HLA allotypes (area under curve, AUC of 0.7-0.9; 0.5 for a random classifier and 1.0 for a perfect classifier), [162][163][164] but perform poorly for less-studied HLA allotypes, such as those common to the Asian population. 165 There are gaps despite many decades of insights into antigen presentation.…”

Heating-mediated purification of active FGF21 and structure-based design of its variant with enhanced potency

“…To estimate whether the five point-mutations affect immunogenicity, we analyzed the binding affinity of peptides derived from the C-terminal loop (residues 174-209) in the wild type FGF21 and M5 towards major histocompatibility complex (MHC) molecules of T cell by using TepiTool 52 in Immune Epitope Database (IEDB). According to this analysis where binding affinities were represented by IC 50 values, most peptides from both proteins were predicted to have high IC 50 values, suggesting little binding to MHC molecules [53][54][55] (Supplementary Figs. S11, S12).…”

TepiTool: A Pipeline for Computational Prediction of T Cell Epitope Candidates

“…Class II molecules, on the other hand, have an open binding groove, allowing them to bind longer peptides, typically 12 to 20 residues in length. The strength of binding (affinity) of a peptide to an MHC molecule is an important factor that determines potential immunogenicity (Sette et al, 1994).…”