Keystone Epitope Theory proposes that persistent, human-adapted DNA viruses focus postnatal immunity on conserved, functionally linked epitopes and coordinate T, B, and NK cell programs within tissue niches. Here, we read fast-evolving RNA viruses and tumors through that lens. RNA viruses succeed by inflating mutable decoys and controlling peptide–HLA display, so that cytotoxic T cell visibility falls while inhibitory NK tone is preserved; tumors converge on the same interoperability fault lines. Keystone Epitope Theory assumes immunity does not have a single default objective. Across most of the antigenic landscape, the system is optimized to (i) tolerate high-abundance, low-danger exposures at barrier surfaces, (ii) maintain dynamic equilibrium with a small set of co-evolved residents that require coordinated multi-arm control, and (iii) deploy sterilizing effector programs against high-danger acute threats. Because sterilization-oriented inflammation is biologically costly, KET treats these outcomes as an allocation problem under finite metabolic and tissue constraints, where adaptable RNA viruses and tumors succeed when they can misclassify themselves within this operating space, either by attracting attention to mutable decoys or by altering display so genuine cytotoxic ‘wins’ are functionally invisible. We formalize a simple decoy-versus-constrained logic, summarize major forms of antigen display control (e.g., HLA-E/NKG2A; HIV Nef/Vpu), and translate these mechanisms into practical principles: target epitopes with measurable fitness cost, avoid decoys that reinforce inhibitory checkpoints, and restore antigen presentation context when needed so cytotoxic wins are visible to both CTL and NK arms. A one-page primer with mechanistic pointers is provided in Box 1. This ecological framing links mechanisms to design across HIV/HCV/influenza/SARS‑CoV‑2 and tumor immunoediting.
Mallal et al. (Wed,) studied this question.