Tracing virus-specific CD8+ T cell clonotype zonation and function in humans

The current Covid-19 pandemic highlights the need to gain better understanding of precise mechanisms that enable immune control of viral infections. Although it is established that CD8+ T cells are required to suppress viremia, most view these cells simply as ?killer T cells? based almost exclusively on studies of blood. I recently discovered that efficient immune control of HIV is mediated primarily by non-killer resident memory CD8+ T cells, whereas CD8+ T cells with high ?killer instinct? are mainly confined to the vasculature. These observations force a reevaluation of how antiviral CD8+ T cells are distributed anatomically and function in the tissue spaces where most viruses replicate. Using cutting-edge single-cell technologies on unique paired tissue samples from human organ donors, my aim here is to challenge prevailing concepts in the field of adaptive immunology and reassess how and where CD8+ T cells actually target viruses in the human body. My group will first use single-cell barcoding techniques to establish a reference map of CD8+ T cell clones specific for multiple viruses across tissue sites. We will then dissect this information to determine whether distinct resident memory CD8+ T cell clones and/or subsets exhibit differential antiviral functions across tissue sites. In parallel, we will use more mechanistic approaches to define the epigenetic imprints and functional properties of antiviral CD8+ T cells, aiming to determine to what extent these features are shaped by subset fate, anatomical location, and/or the nature of the expressed T cell receptor. A specific emphasis throughout this project will be to translate the emerging knowledge to the field of Covid-19, aiming to understand how CD8+ T cells control SARS-CoV-2. This ambitious but technically feasible project will establish a systematic foundation for future studies of antiviral T cells in humans and inform the development of more effective vaccine platforms to combat future viral threats.