Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London , London, UK.
Institute of Immunology and Immunotherapy, University of Birmingham , Birmingham, UK.
J Exp Med. 2023 Oct 2;220(10). doi: 10.1084/jem.20221653. Epub 2023 Jul 19.
Germinal center (GC) dysregulation has been widely reported in the context of autoimmunity. Here, we show that interleukin 21 (IL-21), the archetypal follicular helper T cell (Tfh) cytokine, shapes the scale and polarization of spontaneous chronic autoimmune as well as transient immunization-induced GC. We find that IL-21 receptor deficiency results in smaller GC that are profoundly skewed toward a light zone GC B cell phenotype and that IL-21 plays a key role in selection of light zone GC B cells for entry to the dark zone. Light zone skewing has been previously reported in mice lacking the cell cycle regulator cyclin D3. We demonstrate that IL-21 triggers cyclin D3 upregulation in GC B cells, thereby tuning dark zone inertial cell cycling. Lastly, we identify Foxo1 regulation as a link between IL-21 signaling and GC dark zone formation. These findings reveal new biological roles for IL-21 within GC and have implications for autoimmune settings where IL-21 is overproduced.
生发中心（GC）失调在自身免疫中被广泛报道。在这里，我们表明白细胞介素 21（IL-21），典型的滤泡辅助 T 细胞（Tfh）细胞因子，塑造了自发慢性自身免疫和短暂免疫诱导的 GC 的规模和极化。我们发现 IL-21 受体缺陷导致 GC 变小，并且严重偏向光区 GC B 细胞表型，并且 IL-21 在选择光区 GC B 细胞进入暗区方面发挥关键作用。先前在缺乏细胞周期调节剂 cyclin D3 的小鼠中报道了光区倾斜。我们证明 IL-21 触发 GC B 细胞中环素 D3 的上调，从而调整暗区惯性细胞循环。最后，我们确定 Foxo1 调节是 IL-21 信号和 GC 暗区形成之间的联系。这些发现揭示了 GC 内 IL-21 的新生物学作用，并对产生过多 IL-21 的自身免疫环境具有影响。
