Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Babraham, UK.
Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), Inserm U1291University of Toulouse, Toulouse, F, CNRS U5282, France.
Aging Cell. 2021 Jan;20(1):e13295. doi: 10.1111/acel.13295. Epub 2021 Jan 2.
Ageing profoundly changes our immune system and is thought to be a driving factor in the morbidity and mortality associated with infectious disease in older people. We have previously shown that the impaired immunity to vaccination that occurs in aged individuals is partly attributed to the effect of age on T follicular helper (Tfh) cell formation. In this study, we examined how age intrinsically affects Tfh cell formation in both mice and humans. We show increased formation of Tfh precursors (pre-Tfh) but no associated increase in germinal centre (GC)-Tfh cells in aged mice, suggesting age-driven promotion of only early Tfh cell differentiation. Mechanistically, we show that ageing alters TCR signalling which drives expression of the Notch-associated transcription factor, RBPJ. Genetic or chemical modulation of RBPJ or Notch rescues this age-associated early Tfh cell differentiation, and increased intrinsic Notch activity recapitulates this phenomenon in younger mice. Our data offer mechanistic insight into the age-induced changes in T-cell activation that affects the differentiation and ultimately the function of effector T cells.
衰老大大地改变了我们的免疫系统，被认为是导致老年人感染性疾病发病率和死亡率的一个驱动因素。我们之前已经表明，老年人中疫苗接种免疫受损部分归因于年龄对滤泡辅助性 T 细胞（Tfh）形成的影响。在这项研究中，我们研究了年龄如何内在地影响小鼠和人类的 Tfh 细胞形成。我们发现 Tfh 前体（pre-Tfh）的形成增加，但老年小鼠中的生发中心（GC）-Tfh 细胞没有相应增加，这表明仅促进了早期 Tfh 细胞分化。从机制上讲，我们发现衰老改变了 TCR 信号，从而驱动 Notch 相关转录因子 RBPJ 的表达。RBPJ 或 Notch 的遗传或化学调节可挽救这种与年龄相关的早期 Tfh 细胞分化，而增加内在 Notch 活性可在年轻小鼠中再现这种现象。我们的数据为 T 细胞激活的年龄诱导变化提供了机制上的见解，这些变化影响效应 T 细胞的分化和最终功能。
