Advances in T-Cell Epitope Engineering

arguments dictate that maximal immune cover of possible foreign pMHC requires each TCR to recognize huge numbers of different peptides (Mason, 1998; Sewell, 2012). This theory is now supported up by direct experimental evidence that shows a single TCR can cross-recognize millions of pMHC molecules as well or better than the native antigen (Sewell, 2012; Wooldridge et al., 2012; Ekeruche-Makinde et al., 2013). Curiously, this extensive T-cell cross-reactivity is strictly compartmentalized based on peptide length (Ekeruche-Makinde et al., 2013). An interesting consequence of the low antigen affinity and high antigen crossreactivity characteristics of TCRs is that many, and perhaps all, cognate antigens could potentially be improved upon. Through rational structural modifications of native blueprint antigens we now know it is possible to engineer “optimal fit antigens” which exhibit logarithmic increases in affinity and immunogenicity. Compared with the native antigens, if these optimal antigens prove more effective at stimulating antigen-specific T-cell populations during experimental priming then the compounds may fundamentally redefine how we think about vaccine design.