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 halflives 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