IL-21 shapes germinal center polarization via light zone B cell selection and cyclin D3 upregulation

Petersone et al. investigate IL-21-dependent germinal center (GC) regulation and reveal key roles for IL-21 in promoting light zone GC B cell selection and controlling dark zone GC B cell proliferation by upregulation of cyclin D3. 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.

Automated summary

Petersone et al. investigate the regulation of germinal centers (GC) by IL-21 and uncover important roles of IL-21 in promoting the selection of light zone GC B cells and controlling the proliferation of dark zone GC B cells through upregulation of cyclin D3. The study shows that IL-21 shapes the size and polarization of autoimmune-induced and immunization-induced GC. IL-21 receptor deficiency leads to smaller and skewed GCs towards a light zone GC B cell phenotype, and IL-21 is crucial for the selection of light zone GC B cells for entry into the dark zone. The study also reveals the link between IL-21 signaling and GC dark zone formation through regulation of Foxo1.