Project B09 - Tracking T cell receptor-dependent imprinting of cellular differentiation states during polyclonal and chronic immune responses

While natural T cell populations are thought to consist of a broad and continuous spectrum of TCR affinities and T cell differentiation states, direct investigation of affinity-dependent T cell differentiation within polyclonal TCR repertoires has so far not been experimentally feasible. We have recently developed novel tools which allow for the first time to track defined polyclonal TCR repertoires with single-TCR resolution throughout the entire course of an immune response. Furthermore, we could experimentally demonstrate that the antigen-specific TCR repertoire from naïve precursor populations indeed entails a very wide range of affinities, and we have built up defined polyclonal TCR repertoires which are representative of physiological polyclonality. In this project, we want to use these tools to decipher how TCR affinity shapes CD8+ T cell fate within polyclonal repertoires during infection and tumor disease. In particular, we aim at dissecting the dynamic interplay of structural TCR affinity and phenotypic plasticity during chronic or repetitive antigen exposure.