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a deterministic method. A peptide is either a binder or is not a binder. A brief reading of
the literature shows that motif matches produce many false positives, and are, in all prob-
ability, producing an equal number of false negatives. Indeed there are many examples
where peptides without both dominant anchors still bind with high affinity. A more accu-
rate description of this phenomenon is to say that MHCs bind peptides with an equilib-
rium binding constant dependent on the nature of the bound peptide's sequence. The
driving forces behind this binding are precisely the same as those driving drug binding.
Within the human population there are an enormous number of different, variant genes
coding for MHC proteins, each exhibiting a different peptide-binding sequence selectiv-
ity. T-cell receptors, in their turn, also exhibit different affinities for pMHC. The com-
bined selectivity of both MHCs and TCRs determines the power of peptide recognition
within the immune system and through this phenomenon the recognition of foreign
pathogens. Experimentally, there are many ways to measure binding affinity. IC
50
values
are the most widely quoted binding affinity measures and are calculated from a competi-
tive binding assay (Ruppert et al. 1993). Once a peptide has bound to an MHC to be
recognized by the immune system, the pMHC complex has to be recognized by one of
the TCRs of the T-cell repertoire. It is generally accepted that a peptide binding to an
MHC may be recognized, by a TCR, if it binds with a pIC
50
greater than a value of
6
.
3.
There is some evidence suggesting that as the MHC binding affinity of a peptide
rises, the greater is probability that it will be a T-cell epitope. The prediction, then, of
MHC binding is both the best understood and, probably, the most discriminating step
in the presentation-recognition pathway. A pragmatic solution to the as yet unsolved
problem of what will be recognized by the TCR, and thus activate the T-cell, is to
greatly reduce the number of possible epitopes using MHC binding prediction, and
then test the remaining candidates using some measure of T-cell activation, such as
T-cell killing or thymidine incorporation.
References
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T lymphocyte epitopes based on HLA class I peptide-binding motifs. Hum. Immunol.
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Bankovich, A.J., Girvin, A.T., Moesta, A.K., and Garcia, K.C. (2004) Peptide register shifting
within the MHC groove, theory becomes reality. Mol. Immunol. 40:1033-1039.
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