Combinatorial Peptide Libraries and Biometric Score Matrices Permit the Quantitative Analysis of Specific and Degenerate Interactions Between Clonotypic TCR and MHC Peptide Ligands

Abstract

The interaction of TCRs with MHC peptide ligands can be highly flexible, so that many different peptides are recognized by the same TCR in the context of a single restriction element. We provide a quantitative description of such interactions, which allows the identification of T cell epitopes and molecular mimics. The response of T cell clones to positional scanning synthetic combinatorial libraries is analyzed with a mathematical approach that is based on a model of independent contribution of individual amino acids to peptide Ag recognition. This biometric analysis compares the information derived from these libraries composed of trillions of decapeptides with all the millions of decapeptides contained in a protein database to rank and predict the most stimulatory peptides for a given T cell clone. We demonstrate the predictive power of the novel strategy and show that, together with gene expression profiling by cDNA microarrays, it leads to the identification of novel candidate autoantigens in the inflammatory autoimmune disease, multiple sclerosis.

Identification of peptides from human pathogens able to cross‐activate an HIV‐1‐gag‐specific CD4+ T cell clone

“…The SI value obtained for each amino acid was reported for each position of the 10mer, from P1 to P10. By assuming independent and additive contribution of each position of a peptide [19], an individual peptide was given a score calculated by adding the individual SI of the 10 amino acids in a decamer [16]. Under this assumption, the score value of the peptide is predictive of its stimulatory potency.…”

“…Under this assumption, the score value of the peptide is predictive of its stimulatory potency. A biometrical analysis was completed as in Zhao et al [16]; by moving a scoring window across the known protein sequences in oneamino acid increments, the matrix was used to score all of the overlapping ten-amino acid peptides in all the protein sequences from human viruses and bacteria contained in the GenPept database. As an example, Fig.…”

“…Synthetic combinatorial libraries (SCL) and in particular positional scanning synthetic combinatorial libraries (PS-SCL) combined with biometrical analysis, a strategy that systematically compares the data derived from a PS-SCL with all the peptide fragments present in protein databases, have been successful in the identification of novel, biologically active agonist peptides for clonotypic TCR of known and unknown specificity [16][17][18]. We used a PS-SCL-based biometrical analysis to explore the antigen specificity of the HIV-1 gag-specific TCC isolated from an HIV-1-seronegative donor and to identify peptide agonists of this TCC from known proteins in human pathogens.…”

Cross-immune tolerance: conception and its potential significance on transplantation tolerance

“…It is well known that antigen specificity is a key feature of TCR recognition during T-cell activation, and therefore, a given antigen only stimulates and activates T cells that express the corresponding clonotypic TCR. However, this dogma has now been challenged by studies using CD4 1 or CD8 1 T-cell clone assays [12][13][14][15] or TCR-transgenic animal models. 16 Mathematical modeling predicts that a mouse may have 1-2310 8 mature T cells in the periphery displaying about 2310 6 different clonotypic TCRs, and each naive T-cell clone is likely to express about 50 copies of a particular TCR.…”

Systematic Analysis of the Combinatorial Nature of Epitopes Recognized by TCR Leads to Identification of Mimicry Epitopes for Glutamic Acid Decarboxylase 65-Specific TCRs

“…These observations indicate that a substitution at a certain residue would induce conformational changes of peptides and may affect other residues. In contrast, a quantitative strategy using combinatorial peptide libraries with a positional scanning format (PS-SCLs) 3 and biometric score matrices dissected and predicted peptide mimicry ligands of a given cognate T cells (18,19). However, the precise effect of successive combinations of residues in the antigenic peptide on recognition of certain TCR has heretofore not been clarified.…”