Entering the Age of Specificity in T Cell Immunity

ABSTRACT The discovery of MHC restriction, the resolution of peptide–MHC structure, and the identification of the T cell receptor gene quickly centered epitope‐level specificity as a core concern of T cell biology. Epitope mapping culminated in functional peptide‐based stimulation assays and tetramer staining, which together provide exquisite resolution of individual responses. Despite these tools, quantitative assessment of epitope‐resolved responses in complex human infections and tumors has rarely been applied at scale. As a result, no epitope‐aware correlates of protection or risk have been established for major infections, and most human T cell profiling still occurs at the level of representative epitopes or bulk assays. In this review, I propose that variation in specificity, defined as distinct epitope‐level responses across individuals, represents a largely untested critical element in our assessment of anti‐pathogen and antitumor immunity. Advances in TCR repertoire profiling and reverse epitope discovery now make formal tests of this hypothesis tractable, and I discuss approaches to determine the extent to which epitope variation underlies the noise and variation of human immune phenotypes.