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

Author:

Petersone Lina1ORCID,Wang Chun Jing1ORCID,Edner Natalie M.1ORCID,Fabri Astrid1ORCID,Nikou Spyridoula-Angeliki1ORCID,Hinze Claudia1ORCID,Ross Ellen M.1ORCID,Ntavli Elisavet1ORCID,Elfaki Yassin1ORCID,Heuts Frank1ORCID,Ovcinnikovs Vitalijs1ORCID,Rueda Gonzalez Andrea1ORCID,Houghton Luke P.1ORCID,Li Hannah M.1ORCID,Zhang Yang2ORCID,Toellner Kai-Michael2ORCID,Walker Lucy S.K.1ORCID

Affiliation:

1. Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London 1 , London, UK

2. Institute of Immunology and Immunotherapy, University of Birmingham 2 , Birmingham, UK

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.

Funder

Wellcome

Medical Research Council

Marie Skłodowska-Curie

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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