The pre-exposure SARS-CoV-2-specific T cell repertoire determines the quality of the immune response to vaccination.

Carina Saggau, Gabriela Rios Martini, Elisa Rosati, Silja Meise, Berith Messner, Ann-Kristin Kamps, Nicole Bekel, Johannes Gigla, Ruben Rose, Mathias Voß, Ulf M Geisen, Hayley M Reid, Melike Sümbül, Florian Tran, Dennis K Berner, Yascha Khodamoradi, Maria J G T Vehreschild, Oliver Cornely, Philipp Koehler, Andi Krumbholz, Helmut Fickenscher, Oliver Kreuzer, Claudia Schreiber, Andre Franke, Stefan Schreiber, Bimba Hoyer, Alexander Scheffold, Petra Bacher
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Immunity (Cambridge, Mass.)
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SARS-CoV-2 infection and vaccination generates enormous host-response heterogeneity and an age-dependent loss of immune-response quality. How the pre-exposure T cell repertoire contributes to this heterogeneity is poorly understood. We combined analysis of SARS-CoV-2-specific CD4<sup>+</sup> T cells pre- and post-vaccination with longitudinal T cell receptor tracking. We identified strong pre-exposure T cell variability that correlated with subsequent immune-response quality and age. High-quality responses, defined by strong expansion of high-avidity spike-specific T cells, high interleukin-21 production, and specific immunoglobulin G, depended on an intact naive repertoire and exclusion of pre-existing memory T cells. In the elderly, T cell expansion from both compartments was severely compromised. Our results reveal that an intrinsic defect of the CD4<sup>+</sup> T cell repertoire causes the age-dependent decline of immune-response quality against SARS-CoV-2 and highlight the need for alternative strategies to induce high-quality T cell responses against newly arising pathogens in the elderly.