Advances in T-Cell Epitope Engineering

T-cells recognize small peptide fragments (p) cradled in multiple major histocompatibility complex (MHC) molecules, termed human leukocyte antigens (HLA) in humans. These membrane-integral pMHC molecules are present on surface of all nucleated cells and allow T-cells to detect aberrant intracellular activity, be this infection with microorganisms or abnormal host biochemistry such as neoplastic division. Scanning of pMHC molecules occurs via the αβ T-cell receptor (TCR), a clonotypic, heterodimeric, and membrane-integral molecule on the T-cell surface (Miles et al., 2011a). TCRs engage pMHC molecules via six highly flexible complementarity determining region (CDR) loops and, upon productive docking with a pMHC molecule, the TCR triggers a myriad of intracellular T-cell signaling cascades (Bridgeman et al., 2012). The binding strength (or affinity) between a TCR and a cognate pMHC is relatively weak across known biological systems with monomeric “dwell times” (or half-lives) typically measured in seconds or microseconds at physiological temperatures (Miles et al., 2010; Bridgeman et al., 2012; Smith et al., 2012). This is in contrast to numerous other biological interactions such as antibodies (van der Merwe and Davis, 2003), interleukins (Morton et al., 1994), lipoproteins (Misra et al., 2001), and structural membrane proteins (Matte et al., 2012) which have half-lives measured in hours-to-days. Overall, TCR/pMHC interactions are fleeting even by the dynamic standards of cell surface interactions (van der Merwe and Davis, 2003). The evolutionary rationale for this striking functional divide can only be speculated upon but likely pertains to the primary function of T-cells. T-cells must scan large numbers of pMHC on multiple cells in series in order to identify and eliminate threats quickly. Effective immunity requires that TCR scanning time must be minimal and antigen coverage maximal. Theoretical 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).

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