How frequently are predicted peptides actually recognized by CD8 cells?

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Detection of antigen-specific CD8 cells frequently relies on the use of peptides that are predicted to bind to HLA Class I molecules or have been shown to induce immune responses. There is extensive knowledge on individual HLA alleles’ peptide-binding requirements, and immunogenic peptides for many antigens have been defined. The 32 individual peptides that comprise the CEF peptide pool represent such well-defined peptide determinants for Cytomegalo-, Epstein–barr-, and Influenza virus. We tested the accuracy of these peptide recognition predictions on 42 healthy human donors that have been high-resolution HLA-typed. According to the predictions, 241 recall responses should have been detected in these donors. Actual testing showed that 36 (15 %) of the predicted CD8 cell responses occurred in the high frequency range, 41 (17 %) in mid-frequencies, and 45 (19 %) were at the detection limit. In 119 instances (49 %), the predicted peptides were not targeted by CD8 cells detectably. The individual CEF peptides were recognized in an unpredicted fashion in 57 test cases. Moreover, the frequency of CD8 cells responding to a single peptide did not reflect on the number of CD8 cells targeting other determinants on the same antigen. Thus, reliance on one or a few predicted peptides provides a rather inaccurate assessment of antigen-specific CD8 cell immunity, strongly arguing for the use of peptide pools for immune monitoring.