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.

SARS-CoV-2 感染和疫苗接种会产生巨大的宿主反应异质性和免疫反应质量的年龄依赖性损失。暴露前 T 细胞库如何导致这种异质性尚不清楚。我们结合分析 SARS-CoV-2 特异性 CD4 ⁺具有纵向 T 细胞受体跟踪的 T 细胞疫苗接种前后。我们确定了与随后的免疫反应质量和年龄相关的强烈的暴露前 T 细胞变异性。高质量的反应，由高亲和力的尖峰特异性 T 细胞的强烈扩增、高白细胞介素 21 产生和特异性免疫球蛋白 G 定义，取决于完整的幼稚库和排除预先存在的记忆 T 细胞。在老年人中，两个隔室的 T 细胞扩增受到严重损害。我们的研究结果表明，CD4 ⁺ T 细胞库的内在缺陷导致针对 SARS-CoV-2 的免疫反应质量随年龄而下降，并强调需要替代策略来诱导针对新出现的病原体的高质量 T 细胞反应在老年人。