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Project B8: Sina Frischholz, doctoral researcher (PhD)

Ex vivo metabolic profiling of human antigen-reactive T cells after yellow fever and SARS-CoV-2 vaccination

The goal of vaccination is to induce sustainable and functional T cell memory (Appay et al., 2008; PMID: 18535580). To do so, it is essential to generate large numbers of memory T cell precursors during the acute phase of the immune response, which then form the pool of resting memory T cells from which secondary immune responses start (Schober et al., 2018 (PMID: 29664573), 2020 (PMID: 32205883)). At the same time, cellular metabolism has a central impact on the fate and function of T cells, influencing their activation, differentiation, proliferation, effector function as well as long-term survival (Reina-Campos et al., 2021; PMID: 33981085). However, the metabolism of T cells during the course of a human immune response is still poorly understood. In this regard, a long-standing unanswered question is whether distinct human T cell memory and effector subsets that were generated in vivo possess unique metabolic signatures that contribute to their complementary function.An important reason for this lack of understanding is that, until recently, it has been methodologically challenging to analyze the metabolism of defined cell populations with subset or single cell resolution. Over the last years, novel technologies have emerged that could take metabolic profiling of cellular subsets to the next level (Seydel, 2021; PMID: 34862499). For T cells, analysis of single-cell energetic metabolism by profiling translation inhibition (‘SCENITH’) represents a particularly promising technology, since it is compatible with ex vivo investigation of human antigen-specific T cells via flow cytometry (Argüello et al., 2020; PMID: 33264598). This project aims at using SCENITH to perform, for the first time, ex vivo metabolic profiling of human antigen-specific T cell responses with a subset resolution. To this end, we will investigate antigen-specific T cell responses induced by yellow fever and SARS-CoV-2 mRNA vaccination. Gained insights may provide a metabolic framework to instruct vaccine development for induction of long-lasting and functional T cell responses.