Petersone, Lina; Wang, Chun Jing; Edner, Natalie M; Fabri, Astrid; Nikou, Spyridoula-Angeliki; Hinze, Claudia; Ross, Ellen M; ... Walker, Lucy SK; + view all Petersone, Lina; Wang, Chun Jing; Edner, Natalie M; Fabri, Astrid; Nikou, Spyridoula-Angeliki; Hinze, Claudia; Ross, Ellen M; Ntavli, Elisavet; Elfaki, Yassin; Heuts, Frank; Ovcinnikovs, Vitalijs; Rueda Gonzalez, Andrea; Houghton, Luke P; Li, Hannah M; Zhang, Yang; Toellner, Kai-Michael; Walker, Lucy SK; - view fewer (2023) IL-21 shapes germinal center polarization via light zone B cell selection and cyclin D3 upregulation. Journal of Experimental Medicine , 220 (10) , Article e20221653. 10.1084/jem.20221653.

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Abstract

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.

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