The Immune Attention Economy: Keystone Epitope Theory and the Strategic Allocation Between Tolerance, Equilibrium, and Sterilization

A central gap in immunology is a mechanistic account of how immune systems prioritize among vast antigenic inputs under finite tissue and metabolic constraints, and how these prioritization rules generate both protection and pathology. Here, we outline Keystone Epitope Theory (KET), which organizes immune responses into tolerance, equilibrium (containment), and sterilization (clearance) programs and proposes that persistent, co-evolved keystone organisms calibrate tissue activation thresholds and immunodominance hierarchies by recurrent display of structurally constrained peptide–HLA geometries. KET predicts two common failure modes. First, drugs and post-translationally modified self-peptides can mimic high-gain keystone or niche-calibrating motifs in a permissive HLA background and tissue niche, producing anatomically patterned recall injury; we formalize this as a Four-Condition Gate. Second, adaptable disruptors, including RNA viruses and tumors, can steer responses toward mutationally permissive decoy epitopes and engineer antigen display to create CTL–NK discordance. Natural SIV infection without disease and exhaustion-associated T-cell differentiation are discussed as regulated equilibrium phenotypes. These mechanisms provide a translational lens on persistent challenges, including immune-mediated drug reactions, autoimmunity, vaccine heterogeneity, HIV vaccine design, tumor immune escape, and post-acute inflammatory syndromes, and motivate experimental strategies centered on epitope-resolved mapping, immunodominance steering, and niche inhibitory set-point measurement.