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

• Published in: Immunity 2022-10, Vol.55 (10), p.1924-1939.e5
• Main Authors: Saggau, Carina, Martini, Gabriela Rios, Rosati, Elisa, Meise, Silja, Messner, Berith, Kamps, Ann-Kristin, Bekel, Nicole, Gigla, Johannes, Rose, Ruben, Voß, Mathias, Geisen, Ulf M., Reid, Hayley M., Sümbül, Melike, Tran, Florian, Berner, Dennis K., Khodamoradi, Yascha, Vehreschild, Maria J.G.T., Cornely, Oliver, Koehler, Philipp, Krumbholz, Andi, Fickenscher, Helmut, Kreuzer, Oliver, Schreiber, Claudia, Franke, Andre, Schreiber, Stefan, Hoyer, Bimba, Scheffold, Alexander, Bacher, Petra
• Format: Article
• Language: English
• Subjects: antigen-reactive T cell enrichment; antigen-specific CD4+ T cells; CD154; CD40L; COVID-19; SARS-CoV-2; TCR tracking; vaccination
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2022.08.003

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+ 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+ 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. [Display omitted] •SARS-CoV-2-specific T cell expansion rate indicates immune-response quality•Naive and memory pre-exposure repertoires inversely predict vaccine-response quality•Pre-existing memory T cells are excluded from high-quality vaccination responses•Impaired antigen-specific pre-exposure T cell repertoire as a hallmark of immune aging Determinants of immune-response quality to SARS-CoV-2 remain poorly defined. Saggau et al. examine spike-specific naive and memory T cells pre- and post-vaccination and track pre-existing memory T cell receptors. They define T cell parameters of high-quality vaccine responses and identify high pre-existing memory and low naive T cell contributions as predictors of low-quality responses, particularly in the elderly.