Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München (TUM), Munich, Germany.
Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München (TUM), Munich, Germany; The Joseph Sun Lab, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Immunity. 2023 Jun 13;56(6):1269-1284.e6. doi: 10.1016/j.immuni.2023.04.010. Epub 2023 May 9.
Repetitive pathogen exposure leads to the dominant outgrowth of T cell clones with high T cell receptor (TCR) affinity to the relevant pathogen-associated antigens. However, low-affinity clones are also known to expand and form immunological memory. While these low-affinity clones contribute less immunity to the original pathogen, their role in protection against pathogens harboring immune escape mutations remains unclear. Based on identification of the TCR repertoire and functionality landscape of naive epitope-specific CD8 T cells, we reconstructed defined repertoires that could be followed as polyclonal populations during immune responses in vivo. We found that selective clonal expansion is governed by clear TCR avidity thresholds. Simultaneously, initial recruitment of broad TCR repertoires provided a polyclonal niche from which flexible secondary responses to mutant epitopes could be recalled. Elucidating how T cell responses develop "from scratch" is informative for the development of enhanced immunotherapies and vaccines.
反复接触病原体可导致 T 细胞克隆的优势生长,这些克隆对相关病原体相关抗原具有高 T 细胞受体 (TCR) 亲和力。然而,低亲和力克隆也已知会扩增并形成免疫记忆。虽然这些低亲和力克隆对原始病原体的免疫贡献较小,但它们在保护携带免疫逃逸突变的病原体方面的作用尚不清楚。基于对幼稚表位特异性 CD8 T 细胞 TCR 谱和功能景观的鉴定,我们重建了可在体内免疫反应中作为多克隆群体进行跟踪的定义性库。我们发现,选择性克隆扩增受明确的 TCR 亲合力阈值控制。同时,初始募集广泛的 TCR 库提供了一个多克隆小生境,从中可以召回对突变表位的灵活二次反应。阐明 T 细胞反应如何“从零开始”发展,对于增强免疫疗法和疫苗的开发具有重要意义。
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