HLA class I alleles confer striking risk for T cell–mediated drug hypersensitivity, yet positive predictive
values are low—typically under 10% and as low as 0.12% for some drug–HLA pairs1,2. We propose
that persistent, human-adapted pathogens—notably herpesviruses—focus postnatal immune memory on
conserved epitopes in the tissue niches where viral control occurs (the Keystone Epitope Theory). The
phylogenetic basis for this proposal is that herpesviruses and their vertebrate hosts have co-adapted over
hundreds of millions of years, and that this co-evolutionary relationship is replayed ontogenetically as each
individual acquires these infections and builds tissue-specific immune memory. When a drug-altered self-
peptide approximates the geometry of such a target and is presented by the same risk HLA in the same niche
at sufficient density, pre-existing tissue-resident memory T cells (TRM) may be recruited, breaching local
regulatory equilibria and driving immunopathology. We synthesize three strands of evidence: (i) heterologous
immunity, in which virus-imprinted TRM cross-recognize drug-modified self; (ii) antigen presentation in the
same tissue where antiviral memory already resides, which helps explain why injury is tissue-restricted; and
(iii) public and private TCR solutions that bridge viral and self targets. Beginning with T cell–mediated drug
hypersensitivity as an empirical anchor, we extend this framework to EBV-associated multiple sclerosis and
transplant rejection, and conclude with proposed experimental validation strategies that may be applicable
more broadly to T cell–mediated hypersensitivity and autoimmunity.
Publication Date: 2026-06-18