Impact of location and genetics on human virus-specific CD8+ T cell differentiation and function

CD8+ T cells are critical to generate immunity to most viral infections.

Studies of human blood have been instrumental to advance our understanding of how CD8+ T cells function and can control different viruses. However, most of CD8+ T cells are not found in the blood, but mainly in tissues.

This fact, together with the notion that humans respond very differently to viral infections, force a re-evaluation of how different factors, such as genetics and localization, affect antiviral CD8+ T cell differentiation and functions across tissues and blood.

We will first use single-cell techniques on unique organ donor samples to establish a reference map of where virus-specific CD8+ T cell clones are preferentially located in the human body (aim 1).

Through innovative live-attenuated yellow fever virus vaccination protocols, we will next track how virus-specific CD8+ T cells develop in draining vs. non-draining lymph nodes compared to the blood (aim 2).

Using the same vaccine platform, we will finally assess the impact of genetics on circulating memory CD8+ T cell differentiation through studies on monozygotic twins (aim 3).

This ambitious, but technically feasible project, will establish a framework for many future immunological studies in the field of antiviral immunity and inform the development of more effective vaccine platforms and immune therapies against future viral threats.