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

  • J Exp Med. 2023 Oct 2;220(10):e20221653. doi: 10.1084/jem.20221653.
Lina Petersone  1 ,  Chun Jing Wang  1 ,  Natalie M Edner  1 ,  Astrid Fabri  1 ,  Spyridoula-Angeliki Nikou  1 ,  Claudia Hinze  1 ,  Ellen M Ross  1 ,  Elisavet Ntavli  1 ,  Yassin Elfaki  1 ,  Frank Heuts  1 ,  Vitalijs Ovcinnikovs  1 ,  Andrea Rueda Gonzalez  1 ,  Luke P Houghton  1 ,  Hannah M Li  1 ,  Yang Zhang  2 ,  Kai-Michael Toellner  2 ,  Lucy S K Walker  1
Affiliations
  • 1. Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London , London, UK.
  • 2. Institute of Immunology and Immunotherapy, University of Birmingham , Birmingham, UK.
PMID: 37466652 DOI: 10.1084/jem.20221653
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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