Fahlquist-Hagert Cecilia, Wittenborn Thomas Rea, Pedersen Mattias Krogh, Jensen Lisbeth, Degn Søren Egedal
Laboratory for Lymphocyte Biology, Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.
iScience. 2024 Sep 4;27(10):110887. doi: 10.1016/j.isci.2024.110887. eCollection 2024 Oct 18.
Autoantibodies generated in germinal centers (GCs) contribute to the pathogenesis of autoimmune diseases. GCs are controlled by specialized FoxP3+ T-follicular regulatory cells (Tfr), but their role in established autoimmunity is unclear. We generated autoimmune bone marrow chimeras in which Tfr could be specifically ablated by diphtheria toxin. Furthermore, we tracked the clonal persistence and evolution of Tfr populations using Confetti reporters. Ablation of Tfr caused increased early plasma cell output, but longer-term ablation did not increase plasma cell levels beyond those of Tfr-sufficient controls, suggesting that Tfr fail to contain chronic autoreactive GC responses. In agreement, Tfr were robustly induced in early autoreactive GCs but then waned. Moreover, we observed polyclonal Tfr expansion when ablating part of the Tfr subset. Hence, under homeostatic conditions, a polyclonal population of Tfr operates to control autoreactivity by limiting the output of plasma cells from GCs, but in chronic autoimmunity, this mechanism fails.
生发中心（GCs）产生的自身抗体促成了自身免疫性疾病的发病机制。GCs受专门的FoxP3 + 滤泡调节性T细胞（Tfr）控制，但其在已建立的自身免疫中的作用尚不清楚。我们构建了自身免疫性骨髓嵌合体，其中Tfr可被白喉毒素特异性消融。此外，我们使用五彩纸屑报告基因追踪Tfr群体的克隆持久性和演变。Tfr的消融导致早期浆细胞输出增加，但长期消融并未使浆细胞水平超过Tfr充足的对照组，这表明Tfr无法控制慢性自身反应性GC反应。与此一致的是，Tfr在早期自身反应性GCs中被强烈诱导，但随后减少。此外，当消融部分Tfr亚群时，我们观察到多克隆Tfr扩增。因此，在稳态条件下，多克隆Tfr群体通过限制GCs中浆细胞的输出发挥作用来控制自身反应性，但在慢性自身免疫中，这种机制失效。
