The challenge and promise of studying human antigen-specific T cells

Each antigen-specific T cell population represents only a small fraction of the total T cell repertoire, yet these populations play a disproportionately large role in immune responses to viruses and cancer and act as key effectors in autoimmune disease. Understanding their behaviour and phenotypes is therefore crucial for elucidating disease mechanisms. The rarity of these cells and the difficulty of isolating them meant that most prior studies examined bulk, unselected T cell populations. Such approaches capture substantial heterogeneity arising from diverse antigen targets, HLA alleles and potential bystander cells, yet have shaped much of our understanding of T cell responses and phenotypes. In this Review, we discuss how a combination of fundamental and emerging technologies now enables the detailed study of antigen-specific T cells. We highlight how insights linking epitope specificity, T cell receptor (TCR) usage and functional profiles across blood and tissues are transforming our understanding of T cell immunity. Furthermore, we emphasize that the widespread adoption of paired TCR sequencing is generating antigen-specific TCR datasets that can serve as durable reference libraries, enabling future studies and immune atlases to annotate and characterize antigen-specific T cell responses within broader datasets.