A blind spot of human T cell immunology: epitope specificity in secondary lymphoid organs

The fate of T cells is determined through the expression of a unique T cell receptor (TCR). TCR epitope specificity drives spatial localization, phenotypic and metabolic plasticity, effector function, as well as the evolution of complex repertoires of T cell clones. However, human immunology is often restricted to the peripheral blood compartment and neglects 'professional' lymphoid organs. Furthermore, despite the generation of single-cell 'atlases', our knowledge of the epitopes that are recognized by human T cells is largely limited to only a handful of antigenic specificities from conventionally studied viruses. So far, this has prevented a holistic understanding of T cell clonotypes that link location-dependent cellular qualities to specific antigen exposures or disease entities. Novel methodologies for high-throughput annotation of T cell epitope specificity and high-resolution mapping of histological context bear the potential to enhance our understanding of basic human T cell biology, to provide a large-scale data resource for the connected field of computational T cell biology, and to facilitate the development of novel or improved vaccines and other immunotherapies.