Keystone Theory: Implications for Effective T and Natural Killer Cell Interoperability

Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells form complementary arms of human immunity, yet their interoperability depends on shared peptide–HLA surfaces and finely tuned checkpoints. \emph{Keystone Epitope Theory} proposes that persistent pathogens and host coevolution have shaped these interfaces, aligning TCR and KIR/NKG2 readouts to sustain coordinated control. Here we synthesise structural, genetic, and functional evidence into twelve \emph{Keystone Propositions} (KP1–KP12) that capture triad integration, quantitative tuning, postnatal imprinting, and viral subversion. We then apply this framework to HIV, presenting fourteen canonical scenarios (S1–S14) that map how constrained epitopes, decoy misdirection, and whole-cell display engineering shape outcomes. This systems overview links peptide geometry, licensing set-points, and immunoregulatory wiring to translational design, providing a decision tree for when CTL and NK arms align, when they are diverted, and how interventions can restore balance. We conclude with a design grammar for vaccines and immunotherapies: avoid decoys, prioritise constrained epitopes, co-present class I and II, respect licensing and imprinting, and normalise display when necessary.